Inhalers with airway disks having discrete airway channels and related disks and methods

ABSTRACT

Dry powder inhalers include radially-extending discrete, typically dose-specific, airway channels serially forming a portion of the inhalation pathway to deliver dry powder to a user using the inhalers.

RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. ProvisionalApplication Ser. No. 61/100,482, filed Sep. 26, 2008, and U.S.Provisional Application Ser. No. 61/148,520, filed Jan. 30, 2009, thecontents of which are hereby incorporated by reference as if recited infull herein.

FIELD OF THE INVENTION

The present invention relates to inhalers, and may be particularlysuitable for dry powder inhalers.

BACKGROUND OF THE INVENTION

Generally described, known single and multiple dose Dry Powder Inhalers(DPIs) are an established alternative to pressurized metered doseinhalers (pMDIs). DPIs can use: (a) individual pre-measured doses inblisters containing the drug, which can be inserted into the deviceprior to dispensing; or (b) bulk powder reservoirs which are configuredto administer successive quantities of the drug to the patient via adispensing chamber which dispenses the proper dose. See generally Primeet al., Review of Dry Powder Inhalers, 26 Adv. Drug Delivery Rev., pp.51-58 (1997); and Hickey et al., A new millennium for inhalertechnology, 21 Pharm. Tech., n. 6, pp. 116-125 (1997).

In operation, DPI devices strive to administer a uniform aerosoldispersion amount in a desired physical form of the dry powder (such asa particulate size or sizes) into a patient's airway and direct it to adesired internal deposit site(s).

Unfortunately, some dry powder inhalers can retain some amount of thedrug within the device that may be delivered with another dose of thedrug. This may be particularly prone to happen when a user actuates theinhaler but does not inhale the indexed dose of medicament.

There remains a need for alternative inhalers and/or dose containmentdevices that can be used to deliver medicaments.

SUMMARY OF EMBODIMENTS OF THE INVENTION

Embodiments of the invention provide dose container assemblies that candefine individual airway channels for one or more dose containers thatalign with an inhalation port and capture dry powder from a respectivedose container(s) to define part of the inhalation path to theinhalation port for dispensing the dry powder to a user of the inhaler.

Some embodiments are directed to dry powder dose container assembliesthat include: (a) a dose container disk having opposing upper and lowerprimary surfaces and a plurality of circumferentially spaced apart dosecontainers; and (b) at least one airway disk residing above or below thedose container disk. The at least one airway disk includes a pluralityof circumferentially spaced apart airway channels. The dose containerscan have dry powder sealed therein.

Embodiments of the invention are directed to dry powder dose containerassemblies. The assemblies include: (a) a dose container disk having aplurality of circumferentially spaced apart dose containers, the dosecontainers having dry powder therein (typically a defined or meteredamount); (b) an upper airway disk residing above the dose containerdisk; and (c) a lower airway disk residing below the dose containerdisk. The upper and the lower airway disks each include a plurality ofcircumferentially spaced apart channels and pairs of the lower airwaydisk channels and the upper airway disk channels are aligned with atleast one corresponding dose container therebetween.

The dose container can be used in combination with an inhaler. Theinhaler can include an inhaler body with an inhalation port and apiercing mechanism. In operation, a dose container is indexed to aninhalation position and the piercing mechanism is configured to travelthrough an airway disk aperture, pierce first and second sealant layers,enter, then stay or retract from the dose disk aperture while occludingthe airway disk aperture, thereby allowing dry powder which falls fromthe dose container to reside captured in the airway channel.

In some embodiments, the dose container assembly includes both an upperand lower airway disks and each includes a respective plurality of shortairway channels and a respective plurality of long airway channels, theshort airway channels associated with the first row of dose containerapertures and the long airway channels associated with the second row ofdose container apertures. The short and long airway channels can bearranged to reside adjacent to each other and alternatecircumferentially about the disk.

In some embodiments, pairs of upper and lower airway disk channelscooperate to define a curvilinear airflow path to inhibit undesiredspillage of the dry powder from the inhaler (e.g., provide a sink trapconfiguration).

Other embodiments are directed to dry powder inhalers. The inhalersinclude an inhaler body with an inhalation port, a dose containerassembly held in the inhaler body, a dose container opening mechanismconfigured to open a dose container in a dispensing position in theinhaler, and an indexing mechanism configured to rotate the dosecontainer assembly into the dispensing position.

The dose container assembly includes a dose container disk having aplurality of circumferentially spaced apart apertures with dry powdertherein. The dose container assembly also includes a lower airway diskhaving a plurality of airway channels with upwardly extending sidewallsresiding under the dose container disk, each of the lower airwaychannels being in communication with at least one dose containeraperture, whereby the lower airway disk channels define a plurality ofspaced apart single-use or multi-use inhalation delivery paths thatserially communicate with the inhalation port to thereby provideprotection from inadvertent overdose.

The dose container assembly includes: (a) a dose container disk havingopposing upper and lower primary surfaces and a plurality ofcircumferentially spaced apart apertures with first and second sealantlayers attached to the upper and lower primary surfaces of the dosecontainer disk and defining respective floors and ceilings of the dosecontainer apertures to form dose containers holding dry powder therein;(b) an upper airway disk residing above the dose container disk, theupper airway disk comprising a plurality of circumferentially spacedapart channels with downwardly extending sidewalls; and (c) a lowerairway disk residing under the dose container disk, the lower airwaydisk comprising a plurality of circumferentially spaced apart channelswith upwardly extending sidewalls. Pairs of the lower airway diskchannels and the upper airway disk channels are aligned with at leastone corresponding dose container therebetween.

Yet other embodiments are directed to methods of operating an inhaler.The methods include: (a) providing a dose container ring havingstaggered concentric dose container apertures sealed by upper and lowersealant layers residing over and under the apertures respectively todefine sealed dose containers, the dose container ring attached to anairway channel disk having a plurality of circumferentially spaced apartairway channels, at least one for each dose container; (b) rotating thedose container ring and disk together to present a respective dosecontainer and a corresponding airway channel to a dispensing position inthe inhaler; (c) advancing a piercing mechanism to open both sealantlayers and release dry powder from the dose container to thecorresponding airway channel; (d) leaving the piercing mechanism in anextended position or at least partially retracting the piercingmechanism; (e) fully retracting the piercing mechanism from the airwaydisk aperture after the step of leaving; and (f) isolating the airwaychannel associated with the released dry powder from an inhalation flowpath so that the channel is reused only once or is not used for anysubsequent inhalation delivery.

Additional embodiments are directed to methods of fabricating a dosecontainer assembly. The methods include: (a) providing a dose containerdisk having upper and lower primary surfaces with a plurality ofcircumferentially spaced apart apertures; (b) attaching a sealant layerto one of the upper or lower primary surfaces of the dose containerdisk; (c) filling the dose container disk apertures with dry powder; (d)attaching a sealant layer to the other primary surface of the dosecontainer to provide sealed dose containers; (e) placing the dosecontainer disk between upper and lower airway disks; (f) aligning thedose containers with circumferentially spaced apart airway channels onupper and lower airway disks so that each dose container is incommunication with one of the airway channels in both the upper andlower disks; and (g) attaching the upper and lower airway disks tosandwich the dose container disk therebetween.

In some embodiments, the dose container assemblies can be configured toallow for operation irrespective of orientation and to capture the dosefrom a respective dose container whether the inhaler device is heldright side-up or down so that the dry powder is retained in therespective airway path and the inhaler is thereby resistant tooverdosing. In some embodiments, the inhalers can also provide overdoseprotection to inhibit dispensing accumulated doses released fromdifferent dose containers.

Some embodiments are directed to dry powder dose container assembliesthat include: (a) a first dose container disk having opposing upper andlower primary surfaces and a plurality of circumferentially spaced apartdose containers; (b) a second dose container disk stacked on the firstdose container disk; and (c) at least one airway disk residing above orbelow the first or second dose container disk. The at least one airwaydisk includes a plurality of circumferentially spaced apart airwaychannels.

It is noted that aspects of the invention described with respect to oneembodiment, may be incorporated in a different embodiment although notspecifically described relative thereto. That is, all embodiments and/orfeatures of any embodiment can be combined in any way and/orcombination. Applicant reserves the right to change any originally filedclaim or file any new claim accordingly, including the right to be ableto amend any originally filed claim to depend from and/or incorporateany feature of any other claim although not originally claimed in thatmanner. These and other objects and/or aspects of the present inventionare explained in detail in the specification set forth below.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A is a front perspective view of an inhaler with a cover accordingto some embodiments of the present invention.

FIG. 1B is a front perspective of the inhaler shown in FIG. 1A with thecover in an open position according to some embodiments of the presentinvention.

FIG. 2A is a top perspective view of an exemplary dose containerassembly according to some embodiments of the present invention.

FIG. 2B is an exploded view of the assembly shown in FIG. 2A.

FIG. 2C is a partial cutaway view of airway channels aligned with twodose containers according to some embodiments of the present invention.

FIG. 2D is a top perspective view of another exemplary dose containerassembly according to some embodiments of the present invention.

FIG. 2E is an exploded view of the dose container assembly shown in FIG.2D according to embodiments of the present invention.

FIG. 2F is an exploded view of a dose container assembly with stackeddose disks according to embodiments of the present invention.

FIG. 2G is a partial cutaway view of airway channels aligned with twoconcentric rows of staggered dose containers according to someembodiments of the present invention.

FIG. 3A is a top perspective view of a dose container ring according tosome embodiments of the present invention.

FIG. 3B is a top perspective view of a dose container ring according tosome other embodiments of the present invention.

FIG. 3C is a partial cutaway view of a single dose container accordingto some embodiments of the present invention.

FIG. 3D is a partial cutaway view of a single dose container accordingto some embodiments of the present invention.

FIG. 4A is a greatly enlarged top perspective view of a lower airwaydisk according to some embodiments of the present invention.

FIG. 4B is a top view of a lower airway disk according to someembodiments of the present invention.

FIG. 4C is a bottom view of an exemplary lower airway disk.

FIG. 5A is a greatly enlarged top perspective view of an upper airwaydisk according to some embodiments of the present invention.

FIG. 5B is a greatly enlarged perspective view of an upper airway diskaccording to other embodiments of the present invention.

FIG. 6 is a greatly enlarged partial view of the dose container assemblyshown in FIG. 2A according to embodiments of the present invention.

FIGS. 7A-7C are partial cutaway views of a dose container assembly in aninhaler cooperating with a piercing mechanism having a three-stageoperation sequence according to some embodiments of the presentinvention.

FIG. 8A is a bottom perspective partial cutaway view of an inhaler witha dose container assembly configured so that the outer ring of dosecontainers are aligned with airway channels in disks that have “sinktraps” to inhibit spillage according to some embodiments of the presentinvention.

FIG. 8B is a side perspective view of the device shown in FIG. 8Aillustrating the inner row of dose containers are aligned with airwaychannels in disks that define “sink traps” to inhibit spillage accordingto some embodiments of the present invention.

FIG. 9A is a top perspective view of a dose container assembly andpiercing mechanism according to some embodiments of the presentinvention.

FIG. 9B is a top view of the device shown in FIG. 9A.

FIG. 9C is a side view of the device shown in FIG. 9A.

FIG. 10 is a partial exploded view of the device shown in FIG. 9Aaccording to some embodiments of the present invention.

FIG. 11 is a top assembled view of the portion of the device shown inFIG. 10.

FIG. 12 is a side section view taken along lines 12-12 of FIG. 11,illustrating an outer ring actuation according to some embodiments ofthe present invention.

FIG. 13 is a top assembled view of the portion of the device shown inFIG. 10.

FIG. 14 is a side section view taken along lines 14-14 of FIG. 13,illustrating an inner ring actuation according to embodiments of thepresent invention.

FIG. 15A is a top view of a dose container ring according to someembodiments of the present invention.

FIG. 15B is a partial enlarged fragmentary view of the ring shown inFIG. 15A.

FIG. 16 is a side view of the ring shown in FIG. 15A.

FIG. 17A is a greatly enlarged partial cutaway view of an inhaler withdiscrete airway channels for each dose container and a long airway pathaccording to some embodiments of the present invention.

FIGS. 17B-17D are greatly enlarged partial cutaway side perspectiveviews of an inhaler with a biasing mechanism according to embodiments ofthe present invention.

FIG. 17E is a greatly enlarged cutaway view of an airflow path in aninhaler and secure airpath joint provided by a biasing mechanism such asthat shown, for example, in FIG. 17B-17D or 17F and 17G according toembodiments of the present invention.

FIG. 17F is a perspective partial cutaway view of an inhaler with analternate biasing mechanism (shown inverted from normal orientation)according to embodiments of the present invention.

FIG. 17C is an additional perspective view of the biasing mechanismshown in FIG. 17F.

FIG. 18A is a greatly enlarged partial cutaway view of an inhaler withdiscrete airway channels and a short airway path according to someembodiments of the present invention.

FIG. 18B is a greatly enlarged partial cutaway view of the inhaler shownin FIG. 18A illustrating an indexing mechanism according to someembodiments of the present invention.

FIG. 18C is a greatly enlarged partial cutaway view of an inhaler withdiscrete airway channels and a short airway path according to someembodiments of the present invention.

FIG. 18D is a greatly enlarged partial cutaway view of the inhaler shownin FIG. 18C illustrating an indexing mechanism according to someembodiments of the present invention.

FIG. 18E is an exploded side perspective view of components of theindexing mechanism shown in FIGS. 18C and 18D.

FIG. 18F is an enlarged side perspective view of some assembledcomponents of the inhaler devices shown in FIG. 18E.

FIG. 19A is an enlarged partial section view of an alternate piercingmechanism for the dose containers according to some embodiments of thepresent invention.

FIG. 19B is an enlarged partial section view of a piercing mechanismsimilar to that shown in FIG. 19A according to some embodiments of thepresent invention.

FIG. 19C is a partial front schematic view of a piercing mechanism witha fluted piercer according to some embodiments of the present invention.

FIG. 19D is an end view of the device shown in FIG. 19C.

FIG. 19E is a partial front schematic view of another fluted piercerconfiguration according to some embodiments of the present invention.

FIG. 19F is an end view of an exemplary four lobe fluted pierceraccording to some embodiments of the present invention.

FIG. 19G is a partial cutaway schematic illustration of an inhaler witha piercing configuration according to some embodiments of the presentinvention.

FIG. 20 is an enlarged partial section view of an inhaler havinggenerally “U” shaped inhalation flow paths according to embodiments ofthe present invention.

FIG. 21 is a flow chart of exemplary operations that can be used tooperate an inhaler according to some embodiments of the presentinvention.

FIG. 22 is a flow chart of operations that can be used to fabricate orassemble a dose container assembly according to some embodiments of thepresent invention.

DESCRIPTION OF EMBODIMENTS OF THE INVENTION

The present invention will now be described more fully hereinafter withreference to the accompanying figures, in which embodiments of theinvention are shown. This invention may, however, be embodied in manydifferent forms and should not be construed as limited to theembodiments set forth herein. Like numbers refer to like elementsthroughout. In the figures, certain layers, components or features maybe exaggerated for clarity, and broken lines illustrate optionalfeatures or operations unless specified otherwise. In addition, thesequence of operations (or steps) is not limited to the order presentedin the figures and/or claims unless specifically indicated otherwise. Inthe drawings, the thickness of lines, layers, features, componentsand/or regions may be exaggerated for clarity and broken linesillustrate optional features or operations, unless specified otherwise.Features described with respect to one figure or embodiment can beassociated with another embodiment of figure although not specificallydescribed or shown as such.

It will be understood that when a feature, such as a layer, region orsubstrate, is referred to as being “on” another feature or element, itcan be directly on the other feature or element or intervening featuresand/or elements may also be present. In contrast, when an element isreferred to as being “directly on” another feature or element, there areno intervening elements present. It will also be understood that, when afeature or element is referred to as being “connected”, “attached” or“coupled” to another feature or element, it can be directly connected,attached or coupled to the other element or intervening elements may bepresent. In contrast, when a feature or element is referred to as being“directly connected”, “directly attached” or “directly coupled” toanother element, there are no intervening elements present. Althoughdescribed or shown with respect to one embodiment, the features sodescribed or shown can apply to other embodiments.

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention. Asused herein, the singular forms “a”, “an” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise. It will be further understood that the terms “comprises”and/or “comprising,” when used in this specification, specify thepresence of stated features, steps, operations, elements, and/orcomponents, but do not preclude the presence or addition of one or moreother features, steps, operations, elements, components, and/or groupsthereof. As used herein, the term “and/or” includes any and allcombinations of one or more of the associated listed items.

Spatially relative terms, such as “under”, “below”, “lower”, “over”,“upper” and the like, may be used herein for ease of description todescribe one element or feature's relationship to another element(s) orfeature(s) as illustrated in the figures. It will be understood that thespatially relative terms are intended to encompass differentorientations of the device in use or operation in addition to theorientation depicted in the figures. For example, if a device in thefigures is inverted, elements described as “under” or “beneath” otherelements or features would then be oriented “over” the other elements orfeatures. Thus, the exemplary term “under” can encompass both anorientation of over and under. The device may be otherwise oriented(rotated 90 degrees or at other orientations) and the spatially relativedescriptors used herein interpreted accordingly. Similarly, the terms“upwardly”, “downwardly”, “vertical”, “horizontal” and the like are usedherein for the purpose of explanation only unless specifically indicatedotherwise.

It will be understood that although the terms “first” and “second” areused herein to describe various components, regions, layers and/orsections, these regions, layers and/or sections should not be limited bythese terms. These terms are only used to distinguish one component,region, layer or section from another component, region, layer orsection. Thus, a first component, region, layer or section discussedbelow could be termed a second component, region, layer or section, andvice versa, without departing from the teachings of the presentinvention. Like numbers refer to like elements throughout.

Unless otherwise defined, all terms (including technical and scientificterms) used herein have the same meaning as commonly understood by oneof ordinary skill in the art to which this invention belongs. It will befurther understood that terms, such as those defined in commonly useddictionaries, should be interpreted as having a meaning that isconsistent with their meaning in the context of the specification andrelevant art and should not be interpreted in an idealized or overlyformal sense unless expressly so defined herein. Well-known functions orconstructions may not be described in detail for brevity and/or clarity.

In the description of the present invention that follows, certain termsare employed to refer to the positional relationship of certainstructures relative to other structures. As used herein, the term“front” or “forward” and derivatives thereof refer to the general orprimary direction that the dry powder travels to be dispensed to apatient from a dry powder inhaler; this term is intended to besynonymous with the term “downstream,” which is often used inmanufacturing or material flow environments to indicate that certainmaterial traveling or being acted upon is farther along in that processthan other material. Conversely, the terms “rearward” and “upstream” andderivatives thereof refer to the direction opposite, respectively, theforward or downstream direction.

The term “deagglomeration” and its derivatives refer to flowing orprocessing dry powder in the inhaler airflow path to inhibit the drypowder from remaining or becoming agglomerated or cohesive duringinspiration.

The inhalers and methods of the present invention may be particularlysuitable for holding a partial or bolus dose or doses of one or moretypes of particulate dry powder substances that are formulated for invivo inhalant dispersion (using an inhaler) to subjects, including, butnot limited to, animal and, typically, human subjects. The inhalers canbe used for nasal and/or oral (mouth) respiratory inhalation delivery,but are typically oral inhalers.

The terms “sealant”, “sealant layer” and/or “sealant material” includesconfigurations that have at least one layer of at least one material andcan be provided as a continuous layer that covers the entire uppersurface and/or lower surface or may be provided as strips or pieces tocover portions of the device, e.g., to reside over at least a target oneor more of the dose container apertures. Thus, terms “sealant” and“sealant layer” includes single and multiple layer materials, typicallycomprising at least one foil layer. The sealant or sealant layer can bea thin multi-layer laminated sealant material with elastomeric and foilmaterials. The sealant layer can be selected to provide drug stabilityas they may contact the dry powder in the respective dose containers.

The sealed dose containers can be configured to inhibit oxygen andmoisture penetration to provide a sufficient shelf life.

The term “primary surface” refers to a surface that has a greater areathan another surface and the primary surface can be substantially planaror may be otherwise configured. For example, a primary surface caninclude protrusions or recessions, such as where some blisterconfigurations are used. Thus, a disk can have upper and lower primarysurfaces and a minor surface (e.g., a wall with a thickness) thatextends between and connects the two.

The dry powder substance may include one or more active pharmaceuticalconstituents as well as biocompatible additives that form the desiredformulation or blend. As used herein, the term “dry powder” is usedinterchangeably with “dry powder formulation” and means that the drypowder can comprise one or a plurality of constituents, agents oringredients with one or a plurality of (average) particulate sizeranges. The term “low-density” dry powder means dry powders having adensity of about 0.8 g/cm³ or less. In particular embodiments, thelow-density powder may have a density of about 0.5 g/cm³ or less. Thedry powder may be a dry powder with cohesive or agglomerationtendencies.

The term “filling” means providing a bolus or sub-bolus metered amountof dry powder. Thus, the respective dose container is not required to bevolumetrically full.

In any event, individual dispensable quantities of dry powderformulations can comprise a single ingredient or a plurality ofingredients, whether active or inactive. The inactive ingredients caninclude additives added to enhance flowability or to facilitateaerosolization delivery to the desired target. The dry powder drugformulations can include active particulate sizes that vary. The devicemay be particularly suitable for dry powder formulations havingparticulates which are in the range of between about 0.5-50 μm,typically in the range of between about 0.5 μm-20.0 μm, and moretypically in the range of between about 0.5 μm-8.0 μm. The dry powderformulation can also include flow-enhancing ingredients, which typicallyhave particulate sizes that may be larger than the active ingredientparticulate sizes. In certain embodiments, the flow-enhancingingredients can include excipients having particulate sizes on the orderof about 50-100 μm. Examples of excipients include lactose andtrehalose. Other types of excipients can also be employed, such as, butnot limited to, sugars which are approved by the United States Food andDrug Administration (“FDA”) as cryoprotectants (e.g., mannitol) or assolubility enhancers (e.g., cyclodextrine) or other generally recognizedas safe (“GRAS”) excipients.

“Active agent” or “active ingredient” as described herein includes aningredient, agent, drug, compound, or composition of matter or mixture,which provides some pharmacologic, often beneficial, effect. Thisincludes foods, food supplements, nutrients, drugs, vaccines, vitamins,and other beneficial agents. As used herein, the terms further includeany physiologically or pharmacologically active substance that producesa localized and/or systemic effect in a patient.

The active ingredient or agent that can be delivered includesantibiotics, antiviral agents, anepileptics, analgesics,anti-inflammatory agents and bronchodilators, and may be inorganicand/or organic compounds, including, without limitation, drugs which acton the peripheral nerves, adrenergic receptors, cholinergic receptors,the skeletal muscles, the cardiovascular system, smooth muscles, theblood circulatory system, synoptic sites, neuroeffector junctionalsites, endocrine and hormone systems, the immunological system, thereproductive system, the skeletal system, autacoid systems, thealimentary and excretory systems, the histamine system, and the centralnervous system. Suitable agents may be selected from, for example andwithout limitation, polysaccharides, steroids, hypnotics and sedatives,psychic energizers, tranquilizers, anticonvulsants, muscle relaxants,anti-Parkinson agents, analgesics, anti-inflammatories, musclecontractants, antimicrobials, antimalarials, hormonal agents includingcontraceptives, sympathomimetics, polypeptides and/or proteins (capableof eliciting physiological effects), diuretics, lipid regulating agents,antiandrogenic agents, antiparasitics, neoplastics, antineoplastics,hypoglycemics, nutritional agents and supplements, growth supplements,fats, antienteritis agents, electrolytes, vaccines and diagnosticagents.

The active agents may be naturally occurring molecules or they may berecombinantly produced, or they may be analogs of the naturallyoccurring or recombinantly produced active agents with one or more aminoacids added or deleted. Further, the active agent may comprise liveattenuated or killed viruses suitable for use as vaccines. Where theactive agent is insulin, the term “insulin” includes natural extractedhuman insulin, recombinantly produced human insulin, insulin extractedfrom bovine and/or porcine and/or other sources, recombinantly producedporcine, bovine or other suitable donor/extraction insulin and mixturesof any of the above. The insulin may be neat (that is, in itssubstantially purified form), but may also include excipients ascommercially formulated. Also included in the term “insulin” are insulinanalogs where one or more of the amino acids of the naturally occurringor recombinantly produced insulin has been deleted or added.

It is to be understood that more than one active ingredient or agent maybe incorporated into the aerosolized active agent formulation and thatthe use of the term “agent” or “ingredient” in no way excludes the useof two or more such agents. Indeed, some embodiments of the presentinvention contemplate administering combination drugs that may be mixedin situ.

Examples of diseases, conditions or disorders that may be treatedaccording to embodiments of the invention include, but are not limitedto, asthma, COPD (chronic obstructive pulmonary disease), viral orbacterial infections, influenza, allergies, cystic fibrosis, and otherrespiratory ailments as well as diabetes and other insulin resistancedisorders. The dry powder inhalation may be used to deliverlocally-acting agents such as antimicrobials, protease inhibitors, andnucleic acids/oligionucleotides as well as systemic agents such aspeptides like leuprolide and proteins such as insulin. For example,inhaler-based delivery of antimicrobial agents such as antitubercularcompounds, proteins such as insulin for diabetes therapy or otherinsulin-resistance related disorders, peptides such as leuprolideacetate for treatment of prostate cancer and/or endometriosis andnucleic acids or ogligonucleotides for cystic fibrosis gene therapy maybe performed. See e.g. Wolff et al., Generation of Aerosolized Drugs, J.Aerosol. Med. pp. 89-106 (1994). See also U.S. Patent ApplicationPublication No. 20010053761, entitled Method for AdministeringASPB28-Human Insulin and U.S. Patent Application Publication No.20010007853, entitled Method for Administering Monomeric InsulinAnalogs, the contents of which are hereby incorporated by reference asif recited in full herein.

Typical dose amounts of the unitized dry powder mixture dispersed in theinhalers may vary depending on the patient size, the systemic target,and the particular drug(s). The dose amounts and type of drug held by adose container system may vary per dose container or may be the same. Insome embodiments, the dry powder dose amounts can be about 100 mg orless, typically less than 50 mg, and more typically between about 0.1 mgto about 30 mg.

In some embodiments, such as for pulmonary conditions (i.e., asthma orCOPD), the dry powder can be provided as about 5 mg total weight (thedose amount may be blended to provide this weight). A conventionalexemplary dry powder dose amount for an average adult is less than about50 mg, typically between about 10-30 mg and for an average adolescentpediatric subject is typically from about 5-10 mg. A typical doseconcentration may be between about 1-5%. Exemplary dry powder drugsinclude, but are not limited to, albuterol, fluticasone, beclamethasone,cromolyn, terbutaline, fenoterol, β-agonists (including long-actingβ-agonists), salmeterol, formoterol, cortico-steroids andglucocorticoids.

In certain embodiments, the administered bolus or dose can be formulatedwith an increase in concentration (an increased percentage of activeconstituents) over conventional blends. Further, the dry powderformulations may be configured as a smaller administrable dose comparedto the conventional 10-25 mg doses. For example, each administrable drypowder dose may be on the order of less than about 60-70% of that ofconventional doses. In certain particular embodiments, using thedispersal systems provided by certain embodiments of the DPIconfigurations of the instant invention, the adult dose may be reducedto under about 15 mg, such as between about 10 μg-10 mg, and moretypically between about 50 μg-10 mg. The active constituent(s)concentration may be between about 5-10%. In other embodiments, activeconstituent concentrations can be in the range of between about 10-20%,20-25%, or even larger. In particular embodiments, such as for nasalinhalation, target dose amounts may be between about 12-100 μg.

In certain particular embodiments, during inhalation, the dry powder ina particular drug compartment or blister may be formulated in highconcentrations of an active pharmaceutical constituent(s) substantiallywithout additives (such as excipients). As used herein, “substantiallywithout additives” means that the dry powder is in a substantially pureactive formulation with only minimal amounts of othernon-biopharmacological active ingredients. The term “minimal amounts”means that the non-active ingredients may be present, but are present ingreatly reduced amounts, relative to the active ingredient(s), such thatthey comprise less than about 10%, and preferably less than about 5%, ofthe dispensed dry powder formulation, and, in certain embodiments, thenon-active ingredients are present in only trace amounts.

In some embodiments, the unit dose amount of dry powder held in arespective drug compartment or dose container is less than about 10 mg,typically about 5 mg of blended drug and lactose or other additive(e.g., 5 mg LAC), for treating pulmonary conditions such as asthma.Insulin may be provided in quantities of about 4 mg or less, typicallyabout 3.6 mg of pure insulin. The dry powder may be inserted into a dosecontainer/drug compartment in a “compressed” or partially compressedmanner or may be provided as free flowing particulates.

Some embodiments of the invention are directed to inhalers that candeliver multiple different drugs for combination delivery. Thus, forexample, in some embodiments, some or all of the dose containers mayinclude two different drugs or different dose containers may containdifferent drugs configured for dispensing substantially concurrently.

The inhalers can be configured to provide any suitable number of doses,typically between about 30-120 doses, and more typically between about30-60 doses. The inhalers can deliver one drug or a combination ofdrugs. In some embodiments, the inhalers can provide between about 30-60doses of two different drugs (in the same or different unit amounts),for a total of between about 60-120 individual unit doses, respectively.The inhaler can provide between a 30 day to a 60 day (or even greater)supply of medicine. In some embodiments, the inhalers can be configuredto hold about 60 doses of the same drug or drug combination, in the sameor different unit amounts, which can be a 30 day supply (for a twice perday dosing) or a 60 day supply for single daily treatments.

Certain embodiments may be particularly suitable for dispensingmedication to respiratory patients, diabetic patients, cystic fibrosispatients, or for treating pain. The inhalers may also be used todispense narcotics, hormones and/or infertility treatments.

The dose container assembly and inhaler may be particularly suitable fordispensing medicament for the treatment of respiratory disorders.Appropriate medicaments may be selected from, for example, analgesics,e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine;anginal preparations, e.g., diltiazem; antiallergics, e.g.,cromoglycate, ketotifen or nedocromil; antiinfectives e.g.,cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclinesand pentamidine; antihistamines, e.g., methapyrilene;anti-inflammatories, e.g., beclomethasone dipropionate, fluticasonepropionate, flunisolide, budesonide, rofleponide, mometasone furoate ortriamcinolone acetonide; antitussives, e.g., noscapine; bronchodilators,e.g., albuterol, salmeterol, ephedrine, adrenaline, fenoterol,formoterol, isoprenaline, metaproterenol, phenylephrine,phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline,isoetharine, tulobuterol, or(-)-4-amino-3,5-dichloro-α-[[6-[2-(2-pyridinyl)ethoxy]hexyl]methyl]benzenemethanol;diuretics, e.g., amiloride; anticholinergics, e.g., ipratropium,tiotropium, atropine or oxitropium; hormones, e.g., cortisone,hydrocortisone or prednisolone; xanthines, e.g., aminophylline, cholinetheophyllinate, lysine theophyllinate or theophylline; therapeuticproteins and peptides, e.g., insulin or glucagon. It will be clear to aperson of skill in the art that, where appropriate, the medicaments maybe used in the form of salts, (e.g., as alkali metal or amine salts oras acid addition salts) or as esters (e.g., lower alkyl esters) or assolvates (e.g., hydrates) to optimize the activity and/or stability ofthe medicament.

Some particular embodiments of the dose container assembly and/orinhaler include medicaments that are selected from the group consistingof: albuterol, salmeterol, fluticasone propionate and beclometasonedipropionate and salts or solvates thereof, e.g., the sulphate ofalbuterol and the xinafoate of salmeterol. Medicaments can also bedelivered in combinations. Examples of particular formulationscontaining combinations of active ingredients include those that containsalbutamol (e.g., as the free base or the sulphate salt) or salmeterol(e.g., as the xinafoate salt) in combination with an anti-inflammatorysteroid such as a beclomethasone ester (e.g., the dipropionate) or afluticasone ester (e.g., the propionate).

Turning now to the figures, FIGS. 1A and 1B illustrate an example of amulti-dose inhaler 10 with a cover 11 and inhalation port 10 p. Thecover 11 may extend over a top surface of the inhaler to extend downover an inhalation port 10 p of the mouthpiece 10 m, then extendrearward away from the mouthpiece 10 m over a bottom surface of theinhaler. However, this inhaler configuration is shown merely forcompleteness and embodiments of the invention are not limited to thisinhaler configuration as other form factors, covers and inhalation portconfigurations may be used.

FIG. 2A illustrates a dose container assembly 20 with a dose ring ordisk 30 having a plurality of dose containers 30 c. As shown in FIGS. 2Band 2E, in some embodiments, the dose ring or disk 30 can include aplurality of circumferentially spaced apart through apertures 30 a thatform a portion of the dose containers 30 c. As shown in FIG. 2E, thedose containers 30 c can be defined by dose container apertures 30 a andupper and lower sealants 36, 37.

As shown, the dose container assembly 20 includes a lower airway disk 40and an upper airway disk 50. In other embodiments, the dose containerassembly 20 can include the dose container disk 30 and only one of thelower airway disk 40 or the upper airway disk 50. In such aconfiguration, another type of airway can be used for the other side ofthe disk 30, such as, but not limited to, a fixed or “global” upper orlower airway can be used with the individual airways provided by eitheran upper or lower airway disk 50, 40. Also, it is contemplated that theupper and lower airway disks 50, 40 described herein can be reversed fornormal operation (or inadvertently for atypical operation) so that thelower airway disk is the upper airway disk and the upper airway disk isthe lower airway disk.

As shown in FIGS. 2A and 2B, the lower and upper airway disks 40, 50,respectively, include a plurality of circumferentially spaced apartairway channels 41, 51, respectively. Typically, the disks 40, 50include one channel 41, 51 for one dose container 30 c. However, inother embodiments, as shown, for example, in FIG. 2C, a respectiveairway channel 51, 41 from one or both of the disks 50′, 40′ can be incommunication with two or more different dose containers 30 c. Thisconfiguration will allow for (simultaneous) combination delivery of twoor more different dry powders from two or more dose containers 30 c incommunication with the associated one airway channel 51 or 41 and/or arespective airway channel pair. Thus, while embodiments of the inventionare illustrated as releasing only a dose from a single dose container 30c during one delivery, other embodiments allow the inhalers to dispensea combination drug so that two or more dose containers 30 c may use arespective airway channel 41, 51 for delivery.

It is also noted that the disk 30 can have a single dose container 30 ccircumferentially located between aligned dual containers 30 c ₁, 30 c₂. However, in other embodiments, the dose disk 30 can also beconfigured so that the dose disk 30 has radially spaced apart dual (ormore) containers 30 c ₁, 30 c ₂ with a corresponding airway channel41/51 (typically a channel pair) and does not require either the shorterchannels 41, 51 or the single dose containers 30 c. The dose containerscan be arranged in concentric rows of aligned pairs (or more) of dosecontainers. In some embodiments, the combination delivery configurationcan employ dose containers 30 c ₁, 30 c ₂ which can be configured toreside under or over a respective airway channel 41/51, but the airwaychannel 41/51 can angularly extend from a dose container proximate theinner perimeter to a staggered dose container proximate the outerperimeter of the disk as shown in FIG. 2G. However, the airwaychannel(s) can extend over or under two or more dose channels withnon-staggered centerlines.

In other embodiments, as shown in FIG. 2F, two or more dose disks 30 canbe stacked and reside either sandwiched between the airway channel disks40, 50 or can be used with a single airway disk 40/50 and the piercercan be configured to open two or more stacked dose disk containers torelease the medicaments from two or more stacked dose containers andallow inhalation using one or both channels 41, 51.

In other embodiments, the different dose containers in communicationwith the respective airway channel 51, 41 can allow one dose container30 c ₁ to release dry powder to the airway channel 41 and/or 51, then beused again later for another dose container 30 c ₂. Thus, embodiments ofthe invention allow for some or all airway channels 41, 51 to be usedonce or twice (although other configurations may allow for greaternumber of uses).

In some embodiments, the airway channels 41, 51 can define airways thatare not able to release dry powder residing in a respective airwaychannel to a user once the inhaler is indexed again to another positionso that the outer ring of dose containers are aligned with airway disks.The channels can be configured to have “sink traps” to inhibit spillageaccording to some embodiments of the present invention to provideoverdose protection (unless the dual use configuration is used wherebyonly a single other dose may be released using that airway channel(s) asnoted above).

Where two airway disks are used, e.g., both the lower and upper disks40, 50, the inhaler device 10 can be configured to operate even wheninverted and have the same overdose protection feature. Spillage of drypowder from the inhaler 10 as the dose container 30 e is opened can beinfluenced by gravity. For example, for a conventional obround orelliptical mouthpiece shape, there are two primary device orientations(right-side-up and upside-down), embodiments of the invention allow foroperation of the inhaler device in both orientations. In the embodimentshown, for example, in FIG. 2A, this can be accomplished by having anindividual airway section for a respective dose container 30 c (or dosecontainers where combination drug delivery is desired) both above andbelow the target corresponding dose container(s) 30 c.

FIGS. 2A, 2D and 3A illustrate that the dose container disk 30 caninclude 60 dose containers 30 c while FIG. 3B illustrates that the dosecontainer disk 30 can include 30 dose containers 30 c. Greater or lessernumbers of dose containers may be used.

FIG. 2E illustrates that sealant layers 36, 37 may be configured asannular flat rings as shown can be used to seal the top and bottomsurfaces of the dose disk 30. The sealant layers 36, 37 can have thesame or different material(s) and may include foil, polymer(s) and/orelastomer(s), or other suitable material or combinations of materials,including laminates. Typically, the sealant layers 36, 37 are thinflexible sealant layers comprising foil.

The sealant layers 36, 37 (where used) may be provided as asubstantially continuous ring as shown in FIG. 2E or may be attached tothe dose container disk 30 as individual strips or spots of sealant thatcan be placed over and under the apertures 30 a. In other embodiments,sealant layers may be provided on only one primary surface of the dosedisk 30, and the apertures 30 a may be closed on one side rather thanhave through apertures (not shown). In yet other embodiments, the dosedisk 30 can have a blister configuration 130 (FIG. 17A).

FIGS. 2A, 2D, 3A and 3B also illustrate that the dose container disk 30can include at least one indexing notch 34, shown as a plurality ofcircumferentially spaced apart indexing notches 34. A mating componenton one of the other disks 40, 50 can be used to help orient the disks30, 40, 50 relative to each other. For example, one of the airway disks40, 50, typically the lower disk 40, may include an inner wall with anoutwardly radially extending tab 45 (FIGS. 4A, 6) that aligns with andengages one of those notches 34 to position the channels 41, 51 inalignment with the dose containers 30 c. Other alignment means may beused, including, for example, the reverse of the notch and tabconfiguration described (e.g., one or both airway disks 40, 50 can havea notch and the dose container disk 30 can include a tab or othercomponent).

As shown in FIGS. 2B, 2D, 3A and 3B, the dose containers 30 c may bearranged so that they are circumferentially spaced apart in one or morerows. As shown in FIG. 3A, the dose containers 30 c are arranged instaggered concentric rows, a front row 31 at a first radius from acenter of the disk and a back row 32 at a second different radius. Thedose containers 30 c can be arranged so that centerlines of the dosecontainers 30 c of the back row are circumferentially offset from thecenterlines of the dose containers 30 c in the front row by a distance.As shown in FIG. 3A dose containers 30 c on each respective row arespaced apart a distance “D” and the offset of the centerlines of thoseon the back row to those on the front row is “D/2”. The dose containerdisk 30 can be a molded polymer, copolymer or blends and derivativesthereof, or may comprise metal, or combinations thereof, or othermaterials that are capable of providing sufficient moisture resistance.

The dose container disk 30 can have an outer diameter of between about50-100 mm, typically about 65 mm and a thickness of between about 2-5mm, typically about 3 mm. The disk 30 can comprise a cyclic olefin (COC)copolymer. The apertures 30 a can have a diameter of between about 2-5mm, typically about 3 mm and the sidewalls 30 w of the dose containers30 e may have an angle or draft of about 1-3 degrees per side, typicallyabout 1.5 degrees, as shown in FIG. 3D, to facilitate removal from amold (where a molding process is used to form the disk 30). The dosecontainer 30 is configured to be able to protect the powder frommoisture ingress, while providing a desired number of doses in a compactoverall inhaler size. The individual dose container apertures 30 a arespaced apart from each other to allow sufficient seal area and materialthickness for moisture protection of the powder.

Similar to the embodiment shown in FIG. 2E, FIG. 3C illustrates that thedose containers 30 c may be defined by apertures 30 a sealed by sealantlayers 36, 37 over and under the apertures 30 a. As discussed above, thesealant layers 36, 37 can include foil, a polymer and/or elastomer, orother suitable materials or combinations of materials, includinglaminates. In a dry powder medicament inhaler 10, the drug powder isstored in a closed, moisture-resistant space provided by the dosecontainers 30 c.

Embodiments of the invention provide a dose container assembly 20 thatcan provide a suitable seal and facilitate attachment of the airwaydisks 40, 50 to hold the dose ring or disk 30 therebetween. As shown inFIGS. 2D, 2E, in some embodiments, the dose container disk 30 containssealants 36, 37 which may be a continuous layer over the upper and lower(primary) surfaces of the dose disk 30 and the upper and lower airwaydisks 50, 40 can contact the respective sealant and abut the dose disk20 to allow for a tight fit. The exemplary attachment features shown inFIGS. 2A, 2E and 6 can reduce air leakage by allowing a close fit of theairway disks 40, 50 to the dose ring 30. The disks 40, 50 can sandwichthe dose ring 30 and the dose ring can act as the “stop” to set thedepth of engagement of the assembly features on the airway disks 40, 50.Embodiments of the invention provide a feature to index and/or orientthe airway disks 40, 50 relative to the dose ring 30 as discussed above.In addition or alternatively, as shown in FIGS. 2E and 4A, in someembodiments, relatively simple frictional engagement members, such as,but not limited to, “crush ribs” 47 r, on one or both of the airwaydisks 40, 50 may be used to secure their attachment to each other aswill be discussed further below.

FIG. 4A illustrates an example of a lower airway disk 40. As shown, thedisk 40 defines a plurality of circumferentially spaced apart channels41. For the staggered concentric dose container configuration, the disk40 can include alternating long and short airway channels 42, 43,respectively. Each channel 41 includes opposing end portions 41 a, 41 b,one (substantially or entirely) closed end portion 41 a typicallypositioned adjacent the dose container 30 c and one open end portion 41b. The open end portion end portion 41 b can merge into and/or ispositioned adjacent the exit port 10 p and/or mouthpiece 10 m (FIGS.7A-7C) and/or a make-up air port or channel. The intake and flow can bein either direction and the open end 41 b can be configured to faceeither the inner or outer perimeter of the disk 40 (e.g., be eitherpositioned radially innermost or radially outermost on the disk 40). Thechannels 41 include upwardly extending sidewalls 41 w with adjacentpairs of the long and short channels sharing one of the sidewalls 41 w.Optionally, as shown by feature 48 in FIG. 4A aligned with somechannels, all or some of the channels 41 can include a small bleed hole48 that allows air to enter but is sized to inhibit dry powder fromexiting therefrom (the bleed holes 48 are shown only with a few of thechannels 41 for ease of illustration).

FIGS. 4A and 4B also illustrate that the disk 40 can includecircumferentially spaced apart upwardly extending walls or tabs 47. Oneof which can include the radially (outwardly) extending tab 45 discussedabove. The disk 40 can also or alternatively optionally includecircumferentially extending recesses which align with tabs on the upperairway disk 50 to sandwich the dose disk 30 therebetween. The tabs 47can optionally include crush ribs 47 r that matably engage with tabs 57on the upper airway disk 50 to hold the three piece dose disk assembly20 together with sufficient force without requiring and additionalattachment means.

FIGS. 4C, 18D and 20 illustrate that the disk 40 can also include doseindicia 44 so that a user can visually note what dose is being dispensedor a number of doses left in the inhaler. The dose indicia 44 can alignwith a dose reading aperture in the inhaler housing so that a user canvisually assess the dose indicia/information that is visible to a userwhen a respective dose is indexed or is next to be indexed, to thedispensing position. Dose indicia 44 may also or alternatively be placedon the upper disk 50 and aligned with a dose reading aperture (FIG. 20),or on both upper and lower airway disks 50, 40, respectively.

FIG. 18D illustrates that indicia 44 may be placed along the outerperimeter edge of the lower surface of the lower disk 40, and numberedsequentially 1-60. In some embodiments, as shown in FIG. 20, the indicia44 numbering can serially progress to alternate between rows of the dosecontainers 30 where the dose containers are opened in sequence inalternate rows, e.g., number 1 on the outer row, number 2 on the innerrow, number 3 on the outer row (or vice versa) and so on. However, otherdose numbering patterns may be used, depending on the opening sequence(and the number of doses on the disk). That is, this numbering may beappropriate where the inhaler is configured to open a dose container inone row, then open an adjacent dose container in the other row (e.g.,inner to outer ring or outer to inner ring of dose containers), andrepeating this sequence serially, where two rows of dose containers areused. However, other embodiments may open all the inner dose containersor all the outer dose containers, then open the dose containers in theother row or use a different alternating pattern of opening the dosecontainers on the inner and outer rows, and the dose numbering indiciaon the disk 40 and/or 50 can be presented accordingly.

FIG. 5A illustrates an example of an upper airway disk 50. In thisembodiment, the upper airway disk 50 is shown inverted from its normaluse position (and inverted relative to the orientation shown in FIG.2A). As shown, the disk 50 defines a plurality of circumferentiallyspaced apart channels 51. For the staggered concentric dose containerconfiguration, the disk 50 can include alternating long and short airwaychannels 52, 53, respectively. Each channel 51 includes opposing endportions 51 a, 51 b, the closed or substantially closed portion 51 a istypically positioned adjacent the dose container 30 c. The intake andflow can be in either direction and the open end 51 b can be configuredto face either the inner or outer perimeter of the disk 50 (e.g., beeither positioned radially innermost or radially outermost). The other(open) end portion 51 b merges into and/or is positioned adjacent theexit flow path port 10 p and/or mouthpiece 10 m and/or make-up air portor channel. The channels 51 include downwardly extending sidewalls 51 wwith adjacent pairs of the long and short channels sharing one of thesidewalls 51 w. Optionally, as shown by the broken line with respect tofeature 48 in FIG. 5A, one or all of the channels 51 can include a small(air) bleed hole 48 (shown with only a few channels for ease ofillustration) that allows air to enter but is sized to inhibit drypowder from exiting therefrom.

As also shown in FIG. 5A, each channel 51 can include an aperture 55that is configured to reside over (aligned with) a respective dosecontainer 30 c with the upper sealant layer 36 of the dose container 30c residing under the aperture 55. The apertures 55 allow a piercing(e.g., slicing or puncturing) mechanism to extend through the apertureand open the sealant layers 36, 37 (FIG. 3C). As shown in FIG. 5A, theupper disk 50 can also include one or more of indexing ribs 58 and/orinner perimeter gear teeth 59 or other features that can index the diskwithin the inhaler to rotate the disk to provide the different dosecontainers 30 c to a dispensing position and/or position a piercingmechanism over the target dose container for dispensing to open the dosecontainer 30 c. In other embodiments, one or both of these rotating andpositioning mechanisms (or different features) can be provided on thelower disk or the dose disk (not shown).

FIG. 5B illustrates that the disk 50 can include three tabs 57 insteadof four as shown in FIG. 5A (the lower airway disk 40 can also includethree tabs instead of four in this embodiment, see FIGS. 4B, 4C). One ofthe tabs 57 can have a vertically extending orientation rib 56, shown onan inner perimeter surface of the tab 57. The orientation rib 56 can beon the upper disk 50 and may be configured to cooperate with a piercingframe associated with the piercing mechanism fixed in the inhalerhousing so that the orientation rib 56 aligns to the frame to set acorrect initial position according to dose number (e.g., 1) and preventsindexing past the number of doses in the disk assembly 20. Stateddifferently, the orientation rib 56 cooperates with the inhaler housingor components attached thereto to set an initial position of the diskassembly 20 and may also be used to stop the disk assembly from rotatingaround more than once (e.g., more than 360 degrees). In otherembodiments, these functions can be provided by alternate features orcomponents such as the dose counter as described in co-assigned,co-pending U.S. Publication No. 2010-0078021, identified by AttorneyDocket No. 9336-38, the contents of which are hereby incorporated byreference as if recited in full herein.

The indexing of the disk assembly 20 in the inhaler 10 can be about 6degrees for every dose (about 6 degrees for each of 60 doses to arriveat a single rotation of 360 degrees to dispense the 60 doses).

FIG. 5B also illustrates that the apertures 55 can be configured with ageometry that corresponds to the shape of the piercer 100. The apertures55 can be configured to closely surround the piercer 100 (FIG. 20). Thepiercer 100 can be a fluted piercer. As shown, the aperture 55 has threelobes 551 to snugly matably receive a correspondingly shaped three lobe(fluted) piercer 111 (FIGS. 19C/19D). The fluted piercer can have othernumber of lobes, such as, for example four circumferentially spacedapart lobes 111′ as shown in FIG. 19F and the aperture 55 can have acorresponding four lobe shape. The lobes 551 can be in a differentorientation in the inner row versus the outer row, e.g., rotated 180degrees (see also, FIG. 20).

FIGS. 2A and 6 illustrate the dose container assembly 20 integrallyattached together. FIGS. 2B, 4A, and 5A illustrate the exemplary diskcomponents, 30, 40, 50. The tabs 57 of the disk 50 fit into spaces 49 ofthe disk 40 and the tabs 47 of the disk 40 fit into spaces 59 of thedisk 50 with the crush ribs 47 r (where used) firmly abutting the outeredges of tabs 57 to frictionally engage the components together with thedose disk 30 sandwiched therebetween with a flush fit via a relativelyeasy “press-fit” assembly method. The dose container disk 30 is alignedwith the upper and lower airway disks via the (radially outwardextending) tab 45 that engages one of the alignment notches 34 of thedose container ring 30 as discussed above. However, other alignmentfeatures or indicia may be used as well as other attachmentconfigurations.

The upper and lower airway disks 50, 40 (where both are used) can beattached to the dose container disk 30 or the upper and lower disks 50,40 can be attached together with the dose container disk 30 therebetweenso as to reduce any gaps in the airway path defined thereby. The disk 30can be a stop for attachment features on the airway disks 40, 50. Thedisk 30 with the sealants 36, 37 can have substantially planar upper andlower primary surfaces without requiring any attachment features. Thelower portion of the upper airway disk 50 and the upper portion of thelower airway disk 40 can snugly reside directly against the sealant 36,37 on the respective opposing primary surfaces of the dose containerdisk 30 and/or against the primary surfaces of the dose disk 30 so thatthe attachment features/components are only on the upper and/or lowerdisks 50, 40 allowing for a snug and sufficiently air-tight interfacebetween the disks 30, 40, 50 without gaps created by tolerances in otherbuild configurations. The press-fit attachment without use of adhesiveswhile providing for the substantially air-tight interface can beadvantageous and cost-effective. However, as noted above, otherattachment configurations may be used, including, for example,ultrasonic welding, adhesive, laser weld, other friction fit and/ormatable configurations, the use of seals (O-rings, gaskets and the like)between the connection regions of the walls of the airway channelsfacing the dose container 30 c and the sealant layers 36, 37 over and/orunder the dose containers 30 c of the disk, including combinationsthereof, and the like.

As shown in FIGS. 7A-7C, in operation, pairs of upper and lower alignedand radially extending channels 41, 51 can reside one over and one undera respective dose container 30 c and are in fluid communication via theopened dose container 30 c and aperture 30 a. That is, as shown in FIG.7A, a piercing mechanism 100 advances to pierce the upper and lowersealant layers 36, 37, respectively (FIGS. 2E, 3C). The piercingmechanism 100 can be configured to extend and remain in the lower airwaychannel or may (partially or fully) retract before the dispensing afteropening the lower sealant. Also, although shown as extending down topierce the sealant layers, the piercing mechanism 100 can be configuredto extend upward from the bottom. Either way, in some embodiments, thepiercing mechanism 100 can be configured to occlude part of the aperture30 a and/or aperture 55 in the upper (or lower disk).

As shown in FIG. 7B, the piercing mechanism 100 can then partially orfully retract, or stay extended in the lower (or upper) airway channel,depending on the configuration of the mechanism, but is typicallyconfigured to plug and/or cooperate with a member than can plug theaperture 55 of the upper disk 50 (or lower disk 40 if piercing from thebottom) or otherwise occlude this passage 55 so that the piercingmechanism 100 and/or cooperating member substantially blocks, occludes(and/or) seals) the aperture/opening 55 (FIGS. 2A, 5A). In this way, ifthe inhaler is inverted, powder is prevents from spilling out of thechannel 51 because of the blockage provided by the piercing mechanism100. The airflow path 10 f may be any direction from above to below thedose container 30 c or vice versa. The airflow path 10 f that entrainsthe dry powder can extend from the inner perimeter to the outerperimeter or vice versa. FIGS. 7B, 20 illustrate an exemplary airflowpath 10 f direction (shown by the arrow) to allow air to flow in throughthe open end of the bottom channel 41 b on the outer perimeter of thedisk assembly 20 up through the aperture 30 a and out the open end 51 bof the top channel 51 of the disk assembly 20 to the mouthpiece 10 m. Itis also noted that the exit or inlet open end portions of the channels41 b, 51 b may both face the inner perimeter rather than the outerperimeter of the disc assembly 20 as shown in FIGS. 7A-7C (see, e.g.,FIG. 17A).

After dispensing, the piercing mechanism 100 is fully retracted as shownin FIG. 7C and the dose container assembly 20 can be rotated to adispensing position and/or the piercing mechanism 100 can be activatedto open a different dose container 30 c. In operation, the dosecontainer assembly 20 can be radially pushed outward to seal or providea snug exit flow path for the airway channel 41 and/or 51 against anexit flowpath member 10 fm, e.g., that is or merges into the mouthpiece10 m.

FIG. 17A illustrates that a seal 129, such as an O-ring may be used toprovide a sufficiently air-tight path between the airflow exit path10/(or short path 10 s and/or mouthpiece 10 m) and the disk assembly 20.Other disk to exit airpath seals or closure configurations may be used,examples of which are discussed below.

In some embodiments, partial retraction of the piercer 100 can inhibitor prevent powder from falling out of the airway channel when theinhaler 10 is used in the inverted position. As shown, for example, inFIGS. 17A and 17E, to facilitate this operation, clearance between thepiercer head 100 h and the access aperture 55 in the upper airway disk50 can be small and/or snugly receive the piercer head 100 h. Thepiercer mechanism 100 can also be configured to operate with a highlevel of positional accuracy so that the piercer 100 aligns with and isable to cleanly enter the access aperture 55 of each dose container 30 eheld by the disk 30 (on each row, typically alternating between rows).In some embodiments, air leakage at the joint 10 j (FIGS. 17A, 17E)between the fixed airway associated with the mouthpiece 10 m and therotating disk subassembly 20 can be reduced or eliminated to allow forconsistent dose delivery and that leakage, where present, is consistentdose to dose. As discussed with respect to FIG. 17A, the use of acompliant seal (129) may allow this functionality. Also, the disk 20 canbe biased toward the mouthpiece 10 m as discussed above (e.g., pushedradially toward the joint 10 j/mouthpiece 10 m).

FIGS. 17B-17E illustrate an embodiment of the inhaler 10 that can biasthe disk assembly 20 toward the mouthpiece 10 m using a lever assembly80 that can facilitate an accurate, repeatable position of the diskassembly 20 for piercing, as well as control air leakage at themouthpiece joint 10 j. With regard to air leakage, embodiments of theinhaler provide a tight connection that is temporally synchronized withthe time of inhalation, while at other times, e.g., during indexing ofthe disk assembly 20, the inhaler can allow a looser fit whichfacilitates rotation of the disk assembly 20 in the inhaler 10. In thisembodiment, the mouthpiece 10 m resides on the outer perimeter of thedisk assembly 20 with the exit ports of the disk assembly 20 alsoresiding on the outer perimeter of the disk assembly. In otherembodiments, the exit ports of the airway channels can be on the innerperimeter of the disk or otherwise configured or located.

As shown in FIG. 17B, the lever assembly 80 includes a lever arm 81 thatcommunicates with an upper surface of the upper airway disk 50 andextends down a distance to reside closely spaced to an outer perimeterof the disk assembly 20. The lever assembly 80 also includes a finger 82that resides above the disk assembly 20 and extends down toward the diskassembly 20. In the embodiment shown, the lever assembly 80 alsoincludes a loading post 84 that resides proximate an outer perimeter ofthe disk assembly 20. The lever arm 81 includes a recess 83 that isconfigured to receive the finger 82. As the finger 82 resides in therecess 83, the post 84 post pushes the disk 20 radially inward to causesa tight joint 10 j at the time of inhalation (FIG. 17E). The recess 83can have an open perimeter shape and the finger 82 can slidably enterand exit therefrom. The lever arm 81 can define a ramp (inclined in thedirection toward the recess 83) that slidably engages the finger 82 anddirects the finger 82 to move toward the recess 83.

The lever assembly finger 82 is attached to lever 12 n (also labeled as10 l in FIG. 1B) and rotates with respect to the frame 12 in the inhalerhousing, typically upon user actuation of the lever 12 n. When the lever12 n is returned from “actuated” (dosing) position, the finger 82 ispulled out of the recess 83 so that the disk assembly 20 is free torotate to index to a next dispensing position.

Typically during inhalation, the loading post 84 resides radiallyopposite (substantially diametrically opposed to) the mouthpiece 10 m.The lever arm 81 and post 84 do not rotate. This component is affixed toa frame 12 that is attached to the inhaler housing. The finger 82rotates with respect to the frame 12 (and the lever arm 81).

As shown in FIG. 17B, the finger 82 does not contact the lever arm 81during this portion of the stroke cycle of the lever assembly 80 toallow for free rotation during indexing. FIG. 17C illustrates the finger82 moving toward the recess 83. FIG. 17D illustrates the finger 82 inthe recess 83 to bias the disk assembly 20 toward the exit flow pathmember 10 fm. At the moment of inhalation, the finger 82 is advanced toits fullest extent of travel. Indexing (rotation) of the disk assembly20 occurs while the finger 82 is elsewhere in its travel path.Therefore, as shown by the arrows in FIG. 17D, the lever assembly 80 canbias the disk assembly 20 while the finger 82 is at the far extent oftravel to seal the joint 10 j at the proper time (inhalation), whileallowing free movement during indexing (typically also unbiased the restof the time).

It is recognized that, during manufacturing, there may be atolerance-induced mismatch between the diameters of the dose disk 30 andthe upper airway disk 50 of the disk assembly 20. As shown in FIG. 17E,inner or outer sidewall surfaces (shown as outer sidewall surfaces) ofboth of these disks, 30, 50 contact the mouthpiece 10 m when the diskassembly 20 is biased against it. Thus, as shown in FIG. 17E a smallrelief 10 r can be cut or otherwise formed into the proximate orabutting surface of the an exit flowpath member 10 fm (which may be themouthpiece 10 m) at a location that coincides with the dose disk 30 toassure that the upper airway disk 50, which has the greater amount ofcontact surface, is always the part to contact the mouthpiece or exitflowpath member 10 fm communication with the mouthpiece 10 m.

FIGS. 17F and 17G illustrate an alternate embodiment of a biasingmechanism 180 that can bias the disk assembly 20 toward the mouthpiece10 m during inhalation then releasing or disengaging to allow rotationof the disk assembly 20 for indexing. As discussed above, in someembodiments, the inhaler 10 can be configured to rotate the diskassembly 20 a defined angular rotation, such as about 6 degrees, toserially dispense or access dose containers alternately on inner andouter rows. This biasing mechanism 180 can be configured to operate withthe lever 101 similar to that discussed above with respect to the leverassembly 80 but may also be activated using other components orfeatures.

As shown in FIG. 17F, the biasing mechanism 180 can include a post 182that resides proximate an inner perimeter of the dose container diskassembly 20. The post 182 can reside in a circumferentially extendingslot 182 s having an end portion that merges into a slot portion 183that extends radially outward toward the inner perimeter of the dosedisk assembly 20. During and/or just prior to release of the medicamentto a user for inhalation (e.g., “dosing”), the post 182 travels in slot182 s until it reaches slot portion 183 whereby the post moves radiallyand pushes (typically indirectly) against the inner perimeter of thedisk assembly 20 to bias the disk assembly 20 toward the mouthpiece 10 m(as shown by the arrow). The inhaler is shown upside down from normalorientation in FIG. 17F.

FIG. 17G illustrates that the post 182 can communicate with a stationarypost 182 b on an indexing plate or frame 184. In the embodiment shown,the biasing post 182 is configured to contact and push against post 182b causing post 182 b to flex radially outward against the dose containerassembly 20. The two posts 182, 182 b can be configured to projecttoward each other, one upwardly and one downwardly, with the post 182 btypically residing closer to an inner perimeter of the dose diskassembly 20.

The post 182 is typically attached to or in communication with the lever10 l which is accessible by a user. However, the post 182 can be incommunication with other mechanisms that cause the post 182 to move inthe slot 182 s and bias the disk assembly 20 toward the mouthpiece 10 m.

As shown in FIG. 17G, the indexing plate 184 can reside under gears 109g that are associated with the indexer 109. The rotatable gears 109 gcan be held on mounts 110 on a frame member 109 f as shown in FIG. 18E.Generally stated, the gears 109 g communicate with teeth 109 t onindexing post 109 p that can be part of a ramp disk 209 (FIG. 18F) andgear teeth 59 a on the disk assembly 20 (e.g., as shown, on the lowerdisk 40). Turning the indexing post 109 p turns gears 109 g which, inturn, indexes the disk assembly 20. The other gear teeth 59 b (residingcloser to the bottom of the inhaler housing) can communicate withindexing control arms 109 r as shown in FIG. 18D which can help moreprecisely turn the dose container assembly a desired rotational amount.Note that FIGS. 18D and 18E illustrate the inhaler in an invertedorientation from that of normal use. FIG. 18F shows the inhaler in a“normal” use orientation with the dose disk assembly 20 below thepiercers 100 a, 100 b as also shown, for example, in FIG. 18C. Thepiercer(s) 100 a/100 b can be in communication with the ramp disk 209with fin-like ramps 211 as shown in FIG. 18F. In the embodiment shown,the ramp disk cooperates with the piercer to push the piercer into therespective dose containers 30 e. The post 182 is typically attached tothe lever 101 such as shown in FIGS. 17F, 18E and 18F which isaccessible by a user. However, the post 182 can be in communication withother mechanisms that cause the post to move in the slot 182 s and biasthe disk assembly 20 toward the mouthpiece 10 m.

The indexing mechanism 109 shown in FIGS. 17F and 17G is discussedfurther below with respect to FIGS. 18C-18F. However, other indexingconfigurations can be used.

FIG. 19A illustrates one embodiment of a piercing mechanism 100 with acorkscrew piercer 110. In operation the corkscrew moves up and downvertically straight, typically without rotation, to create a desiredopening shape (e.g., circular) through the sealant layers 36, 37. Inother embodiments, the corkscrew may rotate during extension and/ordispensing. In the embodiment shown, the corkscrew piercer 110 canremain in the lower channel 41 while the dry powder is dispensed in theairflow path and the blockage of the aperture 30 a can be provided by aresilient member 120 that is mounted on the corkscrew 110 and moves upand down therewith. The piercing mechanism 100 can have a two stageoperation, fully up (for indexing) and fully down. The most forwardportion of the corkscrew can have a point with a configuration thatcreates a desired cutting configuration into the sealant (e.g., foil).In some embodiments, the corkscrew piercer 110 can cut a shape with atab into the sealant 36, 37, then fold the tab down to release the drypowder. Positioning the corkscrew piercer 110 in the channel 41 duringdispensing may provide improved aerodynamics or shear or impaction flowturbulence for the dry powder. The resilient member 120 can comprise afoam block or other resilient member 120 (such as a hard or rigid memberbiased by a spring) that can be used to seal or plug the aperture 30 a.FIG. 19B illustrates a similar corkscrew piercer 110 that is used with adisk assembly 20 having both upper and lower airway disks 50, 40. Aresilient and/or flexible member 100 p such as a polymeric and/orelastomeric or foam plug can be used to occlude or seal the diskaperture 55.

FIGS. 19C and 19D illustrate a piercing mechanism 100 with a flutedsolid piercer 111. The flute may have a straight flute configuration orthe flute can have a twist or partial twist along it length, e.g., for atwist configuration, the maxima and minima of the lobes can changeaxially along the length of the flute. The flute can have a crosssection with a plurality of lobes, typically three or four lobes, shownas three lobes in FIG. 19C. The fluted configuration may extend only apartial forward length and merge into a constant diameter segment thatresides in and helps occlude or seal the aperture 55 as shown in FIG.19E. In other embodiments, the solid or fluted piercer configuration canmerge into a cap or plug 100 p that resides over and/or in the aperture55 (see, e.g., FIG. 19C). In some embodiments, the twisted flute 111 canremain in the dose container aperture 30 and/or lower disk 40 duringdispensing which may facilitate turbulence and/or compaction in theairway.

FIG. 19D illustrates that the fluted piercer 111 can rotate as itpierces the foil or other sealant material to form a round hole or maybe extended straight without rotation. In other embodiments, the flutedpiercer 111 can be extended or advanced without rotation to pierce thesealant layer(s) 36, 37. FIG. 19E illustrates that the fluted piercer111′ can include a fluted forward portion 111 f with a length “L₁” thatmerges into a solid portion 112 that can have a substantially circularcross-section with a length “L₂”. L₁ is typically longer than L₂. L₁ canhave a length sufficient to allow the forward fluted portion 111 f toreside in the dose container aperture 30 a (typically just below thelower sealant line or in-line with or slightly above or below the lowersurface of the disk 30) and in or through the lower sealant 37 at thesame time, with the solid portion engaging the airway disk aperture 55.

FIG. 19G illustrates a piercing mechanism 100 that can include a plug100 p (similar to that shown in FIG. 19B for the corkscrewconfiguration) that can occlude the passage 55. The plug 100 p can beused with any piercer, including the corkscrew 110 (FIG. 19A) or thesolid fluted piercer 111 (FIG. 19B) or other piercer configuration. Thepiercing head can remain in the lower channel 41 during dispensing asshown in FIG. 19E, or the piercer may retract partially through apassage in the plug (not shown) while leaving the plug 100 p in positionagainst and/or over the aperture or passage 55.

In some embodiments, the fluted piercer 111 can be configured with lobesthat twist along its length (FIG. 19D). For example, the fluted piercer111 can have about 60 degrees of twist along its length such that thelobes of the fluted piercer turn about its circumference. During astraight piercing stroke (straight into and through the sealant), thetwisted fluted piercer 111 can make a fully round hole in the sealant 36and/or 37.

FIG. 20 illustrates substantially U-shaped airpaths that may be createdby the disk assembly 20. The “U” shape is created by the upper diskchannel 51 and the lower disk channel 41 defining the long sides of the“U” which extend in a radial direction across the disk body. As shown,in this embodiment, the outer perimeter of the disk assembly 20 holdsboth the outlet and an inlet for the airflow path 10 f. The “U” shapedflow path (or, in some embodiment, a “partial “U” where only a one ofthe airflow disks 40, 50 is used) can function as a powderdeagglomerator. The particles impact the opposing wall of the airwaydisk channel 51 as they exit the dose container 30 e with sufficientforce to deagglomerate the drug powder.

FIG. 20 also illustrates an example of dry powder particle trajectories10 d entrained in air flow associated with the inspiratory airflow path10 f. After the dry powder exits the dose container 30 c in the airflowpath 101, the air flow and smaller powder particles (101) in the air areable to make the about 90 degree turn while heavier dry powder particles(10 d) bounce off the inner wall 51 w of the upper airway disk channel51 with increasingly shallow angles eventually going more or lessstraight out of the mouthpiece 10 m. The impact of the heavier drypowder against the walls 51 w help deagglomerate the dry powder.Referring again to FIG. 5A, in the dual row dose container 30embodiment, the channels 51 vary in length depending on if the dosecontainer 30 is on the inner or outer row. In some particularembodiments, the airway channels 41, 51 can include alternating shortand long channels (see, e.g., FIG. 5A). The length of the long channel(the channels with the dose container on the inner perimeter where theouter perimeter is the exit location and vice versa if the innerperimeter is the exit location) can between about 5 mm to about 15 mm,typically about 10 mm, the length of the short channel can be betweenabout 3-10 mm, typically about 5 mm, e.g., about 40-70% the length ofthe long channel. The depth (vertical height) of each channel 41, 51 canbe the same or can, in some embodiments vary. Exemplary depths of thechannels 41, 51 are between about 1 mm to about 3 mm, typically about 2mm, but other depths can be used.

The inhaler 10 can include a user-accessible actuator such as a lever,knob, switch, slider, crank, pushbutton or other mechanical and/orelectromechanical device that can index the dose ring or disk 30 torotate the assembly 20 to place one or more dose containers 30 c (FIG.2B) in a dispensing position in an inhalation chamber in fluidcommunication with the inhalation port 10 p (FIG. 1B) and/or cause apiercing mechanism 100 (FIGS. 7A-7C) to open a dose container 30 c inthe front row, then the back row (or vice versa) to release medicamentto an inhalation air flow path for inhalation by a user (as will bediscussed further below). To release the powder for inhalation, thesealed dose container 30 c is opened and connected to an airway 41and/or 51 which is in turn connected to an exit flowpath member 10 fmwhich can be the inhaler mouthpiece 10 m (see, e.g., FIGS. 7A-7C, 17A,17E, 18A) or can merge into the inhaler mouthpiece 10 m. After the drugfalls into the channel 41 or 51 (depending on which orientation theinhaler is in), this is a “used” channel and the drug therein is eitherdelivered (if the user inhales properly and timely) or isolated (if theuser does not inhale and closes the mouthpiece or otherwise causes theindexing of the disk assembly 20), and the “used” channel is indexedwith the opened dose container 30 c so that it cannot be used again orso that it is used again for only the other dose container in the sharedchannel (as discussed with respect to FIG. 2C). Any powder remaining inthe opened dose container is separated from the airway when the nextdose container is indexed into position.

In some embodiments, the portion of the airway provided by the airwaychannel 41 or 51 adjacent to each dose container 30 c is unique to thatindividual dose container 30 c. In this way, any spillage of powder intothe airway will only be available to the mouthpiece and user as long asthat dose container is indexed into connection with the primary(mouthpiece) airway. Indexing to the next dose container will also indexthe adjacent airway section out of connection with the active inhalationairway path, taking any spilled and/or accumulated powder with it.

FIGS. 8A and 8B illustrate another embodiment of an inhaler 10. In thisembodiment, the upper airway channel 51 can be configured as a “sinktrap” Mt path that has a portion of the airflow path that rises and thenturns down or vice versa. That is, as shown, the path 51 t can riseabove the aperture 30 a, then turn to extend downwardly for a distanceto provide additional spill resistance of the dry powder from theairway/inhaler. Similarly, the lower airway channel 41 can be configuredto rise upward a distance downstream of the dose container aperture 30 ato form a “sink trap” 41 t path. In some embodiments, only one of theairway disks (e.g, the upper or the lower 50, 40) have a sink trap pathwhile in others, both disks 40, 50 have airway configurations with sinktraps 41 t, 51 t as shown. The dose container assembly 20 has an alignedchannel pair 41, 51 that are in fluid communication once the respectivedose container is opened 30 c that reside under and over the respectivedose container 30 e and have the sink trap configurations 41 t, 51 t tothat cooperate to form a curvilinear airflow path (e.g., a generally “S”shape, with the “S” layed on its side). The airflow path 101 can extendeither from the outer perimeter toward the inner perimeter or from theinner perimeter toward the outer perimeter.

As also shown in FIGS. 8A and 8B, in this embodiment, the piercingmechanism 100 can include two piercing members 100 a, 100 b, onededicated to opening the first row of dose containers 30 c and anotherfor the second row of dose containers 30 c.

FIGS. 9A-9C and 10-14 illustrate an exemplary inhaler configuration withupper and lower airways forming a sink trap 51 t, 41 t airflow pathaccording to embodiments of the present invention. As shown, thepiercing mechanism 100 can include the two piercing members 100 a, 100 bmounted on a housing that slides over the dose container assembly 20′.The dose container assembly 20′ can rotate under the piercing mechanism100 as a respective dose container(s) 30 c is indexed to a dispensingposition. Similarly, the dose container assembly 20′ can rotate abovethe piercing mechanism if the piercing mechanism is below the dosecontainer assembly 20, 20′.

FIGS. 10, 12 and 14 illustrate that the lower airway disk 40 can includetwo components, an upper member 40 u and a lower member 40 l that attachto define the curvilinear sink trap paths 41 t. Similarly, the upperairway disk 50 can include two components, an upper member 50 u and alower member 501 that attach to define the curvilinear sink trap paths51 t. In particular embodiments, the dry powder can be provided as apre-measured amount of dry powder 200 and sealed in the aperture 30 abetween the sealant layers 36, 37. As shown in FIG. 10, the upper member50 u can include a tab 150 t that engages a slot 150 s in the lowermember 50 l of the airway disk 50 for alignment and/or attachment.

FIG. 12 illustrates a dose container 30 c on the outer row 31 beingopened with the piercing member 100 b and the associated curvilinearairflow path 41 t, 51 t.

FIG. 14 illustrates the piercing member 100 a in position to open a dosecontainer 30 c on the inner row 32 with the associated airflow path 41t, 51 t.

FIGS. 15A, 15B and 16 illustrate an example of a dose container disk orring 30 with two rows of apertures 30 a used for dose containers 30 c.The dose container disk 30 can be relatively thin, such as about 2-4 mmthick. The dose container apertures 30 a can be configured so that theinner row 32 is at least about 2 mm from the outer row 31 and so thatthe inner and outer rows of dose containers are spaced inward from therespective perimeters by about 2 mm. This spacing can provide sufficientmoisture permeability resistance and/or oxygen resistance.

FIG. 17A illustrates on embodiment of an inhaler 10 with a long exit airpath 10 l compared to the shorter flow path in FIG. 18A. In thisembodiment, the airway disks can orient the channels 41, 51 so that theopen ends 41 b, 51 b face and open to the inside of the disk rather thanthe outside. FIG. 17A also illustrates that the dose container disk 30can be configured with blisters 130.

FIG. 17A also illustrates that the piercing mechanism 100 can comprise arotating piercer head 102 configured to pierce a dose container 30 c onthe inner row, then rotate to pierce the adjacent one 30 c on the outerrow.

FIG. 18A illustrates that the inhaler 10 can be configured with apiercing mechanism 100 that moves radially to open a dose container 30 cin one row then move radially inward or radially outward to open a dosecontainer 30 c in the other row. The dose container assembly 20 and/orone or more of the airway disks 40, 50 and dose container disk 30 canalso be configured to axially or otherwise bias (together orindividually) with a wall or walls of an exit airflow path to provide asufficiently tight seal, such as discussed above. FIGS. 18A, 18B alsoillustrate that the inhaler 10 can include an indexing mechanism 109that cooperates with the gear teeth 59 on the inner perimeter of theupper disk 50. Other indexing mechanisms may be used to rotate theassembly 20 to place the different dose containers 30 c in thedispensing position.

FIG. 18C illustrates that the inhaler 10 can be configured with apiercing mechanism 100 that has two piercers 100 a, 100 b, one thatpierces dose containers on the inner row and the other thatpierces/opens dose containers on the outer row. Typically, the piercingmechanism 100 is configured so that a dose container on the outer orinner row is pierced, then a dose container on the opposite row ispierced. The piercers 100 a, 100 b can reciprocate up and down to openthe respective dose container. The dose container assembly 20 and/or oneor more of the airway disks 40, 50 and dose container disk 30 can alsobe configured to axially or otherwise bias (together or individually)with a wall or walls of an exit airflow path to provide a sufficientlytight seal.

FIGS. 18C-18E also illustrate that the inhaler 10 can include anindexing mechanism 109 with gears 109 g that cooperate with an indexingpost 109 p and the disk assembly 20 gear teeth 59 a can reside on theinner perimeter of the lower disk 40. FIG. 18D is shown inverted fromthe normal use orientation shown in FIG. 18C. FIG. 18C-18E also showthat the lower airway disk 40 can include two proximately stacked layersof gear teeth 59 a, 59 b, one of which 59 a cooperates with the post 109p and associated indexing gears 109 g and the other of which 59 b canprovide more precise positioning using arms 109 r as shown in FIG. 18D.Other indexing mechanisms may be used to rotate the assembly 20 to placethe different dose containers 30 c in the dispensing position. The dualpiercers 100 a, 100 b can cooperate with ramp surfaces (fins 211) onramp disk 209. The fins 211 can be arranged as circumferentially offsetfins on two concentric rows that force the respective piercers 100 a,100 b down to pierce sealant 36 and/or 37 (FIG. 2E) in response tocontact with the fins. Additional description of the indexer and dualpiercer are provided in co-pending, co-assigned. U.S. Publication No.2010-0078021, identified by Attorney Docket number 9336-38, the contentsof which are hereby incorporated by reference as if recited in fullherein.

In some embodiments, the mouthpiece port 10 p and an air inlet port (notshown) may be spaced apart about a distance of between about 12-127 mm(about 0.5-5 inches). The inhaler 10 may have a relatively short airintake airpath (measured from where an air intake is disposed to theinhalation port 10 p), such as between about 12-25.4 mm such as shown inFIGS. 7A-7C, 18A and 18C, or a longer air path such as shown in FIG.17A, typically between about 50-127 mm (about 2-5 inches). The shorterair path can be defined to include a short tubular air path extendingbetween the dry powder release location and the inhalation mouthpiecewith a turbulence promoter segment that inhibits agglomeration thatmerges into the inhaler mouthpiece (not shown). The longer air path mayextend across a major portion or substantially all of a width or lengthof the inhaler body. The inner surfaces/shape of the flow path can bepolygonal to facilitate a cyclonic air stream to bounce off the innersurfaces which act as impact surfaces. For additional discussion ofsuitable turbulence promoter configurations, see PCT/US2005/032492,entitled, Dry Powder Inhalers That Inhibit Agglomeration, RelatedDevices and Methods, the contents of which are hereby incorporated byreference as if recited in full herein.

The inhaler 10 can have a body that is a portable, relatively compact“pocket-sized” configuration. In some embodiments, the inhaler body canhave a width/length that is less than about 115 mm (about 4.5 inches),typically less than about 89 mm (about 3.5 inches), and athickness/depth of less than about 51 mm (about 2 inches), typicallyless than about 38 mm (about 1.5 inches). The inhaler body can also beconfigured to be generally planar on opposing primary surfaces tofacilitate pocket storage.

The inhaler can include a circuit that can control certain operations ofthe inhaler 10. The inhaler 10 can include a computer port (not shown).The port may be, for example, an RS 232 port, an infrared dataassociation (IrDA) or universal serial bus (USB), which may be used todownload or upload selected data from/to the inhaler to a computerapplication or remote computer, such as a clinician or other site. Theinhaler 10 can be configured to via a wired or wireless communicationlink (one-way or two-way) to be able to communicate with a clinician orpharmacy for reorders of medicines and/or patient compliance. Theinhaler 10 may also include a second peripheral device communicationport (not shown). The inhaler 10 may be able to communicate via theInternet, telephone, cell phone or other electronic communicationprotocol.

In some embodiments, the circuit can include computer program codeand/or computer applications that communicate additional data to a user(optionally to the display) as noted above and/or communicate withanother remote device (the term “remote” including communicating withdevices that are local but typically not connected during normalinhalant use).

In some embodiments, the circuit can be in communication with a vibratordevice (not shown). The vibrator device can be any suitable vibratormechanism. The vibrator device can be configured to vibrate the drypowder in the airflow path.

In some embodiments, the vibrator device can comprise a transducer thatis configured to vibrate the opened cartridge(s) holding the dry powder.Examples of vibrator devices include, but are not limited to, one ormore of: (a) ultrasound or other acoustic or sound-based sources (above,below or at audible wavelengths) that can be used to instantaneouslyapply non-linear pressure signals onto the dry powder; (b) electrical ormechanical vibration of the walls (sidewalls, ceiling and/or floor) ofthe inhalation flow channel, which can include magnetically inducedvibrations and/or deflections (which can use electromagnets or permanentfield magnets); (c) solenoids, piezoelectrically active portions and thelike; and (d) oscillating or pulsed gas (airstreams), which canintroduce changes in one or more of volume flow, linear velocity, and/orpressure. Examples of mechanical and/or electro-mechanical vibratorydevices are described in U.S. Pat. Nos. 5,727,607, 5,909,829 and5,947,169, the contents of which are incorporated by reference as ifrecited in full herein. Combinations of different vibrating mechanismscan also be used.

In some embodiments, the vibrator device can include a commerciallyavailable miniature transducer from Star Micronics (Shizuoka, Japan),having part number QMB-105PX. The transducer can have resonantfrequencies in the range of between about 400-600 Hz.

In certain embodiments, the inhaler 10 can include visible indicia(flashing light or display “error” or alert) and/or can be configured toprovide audible alerts to warn a user that a dose was properly (and/orimproperly) inhaled or released from the inhaler. For example, certaindry powder dose sizes are formulated so that it can be difficult for auser to know whether they have inhaled the medicament (typically thedose is aerosolized and enters the body with little or no taste and/ortactile feel for confirmation). Thus, a sensor (not shown) can bepositioned in communication with the flow path in an inhaler andconfigured to be in communication with a digital signal processor ormicrocontroller, each held in or on the inhaler. In operation, thesensor can be configured to detect a selected parameter, such as adifference in weight, a density in the exiting aerosol formulation, andthe like, to confirm that the dose was released.

The sealed dose containers 30 c can be configured so that the watervapor transmission rate can be less than about 1.0 g/100 in²/24 hours,typically less than about 0.6 g/100 in²/24 hours and an oxygentransmission rate that is suitable for the dry powder held therein. Thedose container assemblies 20, 20′ can be configured with a stable shelflife of between about 1-5 years, typically about 4 years.

The dose containers 30 c can have a volume (prior to filling andsealing) that is less than about 24 mm³, typically between 5-15 mm³. Thepowder bulk density can be about 1 g/cm³ while the power nominal densitywhen filled (for reference) can be about 0.5 g/cm³. The maximumcompression of a drug by filling and sealing in the dose container 30 ccan be less than about 5%, typically less than about 2%. The maximumheating of drug during the filling and sealing can be maintained to adesirable level so as not to affect the efficacy of the drug or theformulation.

FIG. 21 illustrates exemplary operations that can be used to operate aninhaler according to embodiments of the present invention. The devicecan be configured to have an automated three-stage operation atactuation to inhibit overdose delivery, e.g., it can serially: (a)pierce the sealant layers, (b) release the drug (typically followedclose in time by delivery to a user), and (c) index to the next(unopened) dose container (thus isolating or closing any exit route forthe released dry powder if not inhaled); or (a) index to a target dosecontainer (thus isolating an earlier opened airway channel), (b) piercethe sealant layers and (c) release drug or dry powder from the openeddose container. A dose container ring having a staggered concentricarrangement of dose container apertures sealed by upper and lowersealant layers defining dose containers and attached to an underlyingdisk with a plurality of circumferentially spaced apart airway channels,one for each dose container, is provided (block 300). The dose containerwith the underlying disk is rotated to a dispensing position in theinhaler (block 310). The indexing can rotate the dose disk assemblyabout 6 degrees, repeated about 60 times to access 30 dose containers onthe inner row and 30 dose containers on the outer row while rotatingonly about 360 degrees. The airway channel associated with the releaseddry powder is isolated from the inhalation path so that the used airflowchannel is not used for any subsequent inhalation delivery or is usedonly one more time (block 325).

In some embodiments, a piercing mechanism is advanced to open bothsealant layers and release dry powder from the dose container in thedispensing position to the underlying airway channel (block 320). Thepiercing mechanism can either remain extended or can be partially orfully retracted with the piercing mechanism or cooperating memberthereof occluding the opening to the upper airway channel. In someembodiments, the piercing mechanism can be partially retracted, leavingat least a forward portion in the respective dose container aperture toocclude and/or plug the aperture. The isolating step can be in responseto and/or after either the step of fully retracting the piercingmechanism from the dose container aperture (block 350) or the rotatingstep (block 310) or both.

The method can also optionally include flowably directing the releaseddry powder to a user via the airway channel.

FIG. 22 illustrates exemplary fabrication operations that can be used toassemble a dose container assembly according to embodiments of thepresent invention. As shown, a dose container disk (block 400) withcircumferentially spaced apart through apertures is provided. At leastone sealant layer is attached to the upper or lower primary surface ofthe disk over or under the dose container apertures (block 410) (e.g., acontinuous layer or strips or small pieces of sealant layers can bepositioned over the apertures). The dose container apertures are filledwith dry powder (noting “filled” does not require volumetrically full)(block 420). Typically, the powder is filled to between about 30-75%volume. The sealant layer can be attached to the other primary surfaceof the dose disk to provide sealed dose containers (block 430). The dosecontainer disk can be placed between upper and lower airway disks (block440). The dose containers can be aligned with circumferentially spacedapart airway channels on the airway disks so that each dose container isin communication with a different one of the airway channels in both theupper and lower disks (block 450). The upper and lower disks can beattached to hold the dose container disk therebetween to provide a dosecontainer assembly (block 460).

The following exemplary claims are presented in the specification tosupport one or more devices, features, and methods of embodiments of thepresent invention. While not particularly listed below, Applicantpreserves the right to claim other features shown or described in theapplication.

The foregoing is illustrative of the present invention and is not to beconstrued as limiting thereof. Although a few exemplary embodiments ofthis invention have been described, those skilled in the art willreadily appreciate that many modifications are possible in the exemplaryembodiments without materially departing from the novel teachings andadvantages of this invention. Accordingly, all such modifications areintended to be included within the scope of this invention as defined inthe claims. In the claims, means-plus-function clauses, where used, areintended to cover the structures described herein as performing therecited function and not only structural equivalents but also equivalentstructures. Therefore, it is to be understood that the foregoing isillustrative of the present invention and is not to be construed aslimited to the specific embodiments disclosed, and that modifications tothe disclosed embodiments, as well as other embodiments, are intended tobe included within the scope of the appended claims. The invention isdefined by the following claims, with equivalents of the claims to beincluded therein.

That which is claimed is:
 1. A dry powder dose container assembly,comprising: a dose container disk having opposing upper and lowerprimary surfaces and a plurality of circumferentially spaced apart dosecontainers; and at least one airway disk residing above or below thedose container disk, the at least one airway disk comprising a pluralityof circumferentially spaced apart airway channels, wherein the airwaychannels of the at least one airway disk are elongate and extend in aradial direction across the airway disk, wherein the elongate channelshave opposing first and second end portions, with the first end portionbeing substantially open and the second end portion being substantiallyclosed, and wherein the first end portion resides at an inner or outerperimeter of the disk and the second end portion resides above or belowa respective dose container.
 2. A dry powder dose container assembly,comprising: a dose container disk having opposing upper and lowerprimary surfaces and a plurality of circumferentially spaced apart dosecontainers; and at least one airway disk residing above or below thedose container disk, the at least one airway disk comprising a pluralityof circumferentially spaced apart airway channels, wherein the at leastone airway disk includes a first airway disk and a second airway disk,the first airway disk residing below the dose container disk and thesecond airway disk residing above the first airway disk with the dosecontainer disk therebetween, wherein at least one of the airway channelsof the first airway disk is aligned with a corresponding at least one ofthe airway channels of the second airway disk with at least one dosecontainer therebetween to define cooperating airway channels, andwherein the dose container assembly further comprises dry powder in thedose containers, and wherein the first airway disk airway channels havea floor with a closed surface and a pair of upwardly extendingsidewalls, and wherein the second airway disk has a ceiling withcircumferentially spaced apart apertures, with at least one apertureresiding over each dose container, wherein the second airway diskchannels each include a pair of downwardly extending sidewalls that facethe sidewalls of the first airway disk channels.
 3. A dry powder dosecontainer assembly according to claim 2, wherein the at least one airwaydisk is snugly attached to the dose container disk with a substantiallyair-tight interface therebetween, and wherein the at least one airwaydisk or the dose container disk includes gear teeth on an inner or outerperimeter thereof that cooperate with an indexing mechanism in aninhaler to rotate the dose container assembly to position respectivedose containers at a dispensing position in the inhaler so that, in adispensing position, at least one of the airway channels is in fluidcommunication with (a) a dose container held therebetween and (b) amouthpiece for allowing a user to inhale dry powder released from thedose container using the at least one airway channel as an exit flowpath to the mouthpiece.
 4. A dry powder dose container according toclaim 2, wherein the cooperating channels are cooperating pairs ofairway channels, one upper and one lower channel with the at least onedose container therebetween, the upper and lower channel and thecorresponding dose container defining a single-use or dual-use airwaypath in an inhaler for delivering dry powder from the at least one dosecontainer held therebetween.
 5. A dry powder dose container assemblyaccording to claim 4, wherein the dose container disk further comprises:a plurality of circumferentially spaced apart dose container aperturesextending through the dose container disk that define at least a portionof the dose containers; a first sealant residing over the dose containerapertures; and a second sealant residing under the dose containerapertures.
 6. A dry powder dose container assembly, comprising: a dosecontainer disk having opposing upper and lower primary surfaces and aplurality of circumferentially spaced apart dose containers; and atleast one airway disk residing above or below the dose container disk,the at least one airway disk comprising a plurality of circumferentiallyspaced apart airway channels, wherein the dose container disk includes afirst row of circumferentially spaced apart apertures at a first radiusand a second row of circumferentially spaced apart apertures at a secondradius positioned so that the first and second rows are concentric withrespect to a center of the disk.
 7. A dry powder dose container assemblyaccording to claim 6, wherein the first row of dose container apertureshave radially extending centerlines that are offset circumferentiallyfrom radially extending centerlines of the second row of dose containerapertures.
 8. A dry powder dose container assembly, comprising: a dosecontainer disk having opposing upper and lower primary surfaces and aplurality of circumferentially spaced apart dose containers; and atleast one airway disk residing above or below the dose container disk,the at least one airway disk comprising a plurality of circumferentiallyspaced apart airway channels, wherein the dose container disk has 30dose containers with a corresponding 30 dose disk apertures in the firstrow and 30 dose containers with a corresponding 30 dose disk aperturesin the second row, and wherein the at least one airway disk has 60airway channels configured with alternating channels of first and seconddifferent radial lengths, the first length corresponding to channelsextending from an inner or outer perimeter of the airway disk to dosecontainers in the first row and the second length corresponding tochannels extending from an inner or outer perimeter of the airway diskto dose container apertures in the second row.
 9. A dry powder dosecontainer assembly, comprising: a dose container disk having opposingupper and lower primary surfaces and a plurality of circumferentiallyspaced apart dose containers; and at least one airway disk residingabove or below the dose container disk, the at least one airway diskcomprising a plurality of circumferentially spaced apart airwaychannels, wherein the dose container disk has first and second radiallyspaced apart rows of dose container apertures, one for each of the dosecontainers, wherein the at least one airway disk includes a plurality ofshort airway channels and a plurality of long airway channels, the shortairway channels associated with the first row of dose containerapertures and the long airway channels associated with the second row ofdose container apertures, and wherein the short and long airway channelsreside adjacent each other and alternate circumferentially about thedose disk assembly such that one short channel resides between two longchannels.
 10. A dry powder dose container assembly, comprising: a dosecontainer disk having opposing upper and lower primary surfaces and aplurality of circumferentially spaced apart dose containers; and atleast one airway disk residing above or below the dose container disk,the at least one airway disk comprising a plurality of circumferentiallyspaced apart airway channels, wherein the at least one airway diskincludes a first airway disk and a second airway disk, the first airwaydisk residing below the dose container disk and the second airway diskresiding above the first airway disk with the dose container disktherebetween, wherein at least one of the airway channels of the firstairway disk is aligned with a corresponding at least one of the airwaychannels of the second airway disk with at least one dose containertherebetween to define cooperating airway channels, and wherein the dosecontainer assembly further comprises dry powder in the dose containers,and wherein the cooperating channels are cooperating pairs of channels,with at least one of the airway channels in each cooperating pair ofchannels including a curvilinear airflow path portion that rises a firstdistance above a respective dose container, then turns toward an inneror outer perimeter of the dose container disk for a second distance,then travels down away from the dose container disk for a thirddistance, wherein the third distance is at least the same as the firstdistance, whereby the curvilinear airflow path portion inhibitsundesired spillage of the dry powder from the inhaler.
 11. A dry powderdose container assembly according to claim 8, wherein the at least oneairway disk airway channels each have an open end that all reside on oneof an inner or outer perimeter of the at least one airway disk.
 12. Adry powder dose container assembly, comprising: a dose container diskhaving opposing upper and lower primary surfaces and a plurality ofcircumferentially spaced apart dose containers; and at least one airwaydisk residing above or below the dose container disk, the at least oneairway disk comprising a plurality of circumferentially spaced apartairway channels, wherein the at least one airway disk includes a firstairway disk and a second airway disk, the first airway disk residingbelow the dose container disk and the second airway disk residing abovethe first airway disk with the dose container disk therebetween, whereinat least one of the airway channels of the first airway disk is alignedwith a corresponding at least one of the airway channels of the secondairway disk with at least one dose container therebetween to definecooperating airway channels, and wherein the dose container assemblyfurther comprises dry powder in the dose containers, and wherein thedose container disk and the first and second airway disks have asubstantially circular inner perimeter and the dose container disk andthe first and second airway disks have substantially the same outerdiameters, wherein the dose container disk includes a recess on theinner perimeter thereof, wherein at least one of the first and secondairway disks includes circumferentially spaced apart upwardly ordownwardly extending tabs on the inner perimeter thereof, wherein one ofthe tabs includes a radially extending portion that engages the recessof the dose container disk to orient the dose container disk withrespect to the first and second airway disks, and wherein the tabs of atleast one of the airway disks include crush ribs that engage when thefirst and second airway disks are assembled together, and wherein thefirst and second airway disks are press-fit together to engage the crushribs with the dose container disk sandwiched tightly therebetween toform an integral securely attached assembly.
 13. A dry powder dosecontainer assembly, comprising: a dose container disk having opposingupper and lower primary surfaces and a plurality of circumferentiallyspaced apart dose containers; at least one airway disk residing above orbelow the dose container disk, the at least one airway disk comprising aplurality of circumferentially spaced apart airway channels; and bleedholes in an inner or outer perimeter wall of the at least one airwaydisk, a respective bleed hole in communication with an air inlet paththat merges into a respective airway channel of the at least one airwaydisk.
 14. A dry powder dose container assembly, comprising: a dosecontainer disk having opposing upper and lower primary surfaces and aplurality of circumferentially spaced apart dose containers; and atleast one airway disk residing above or below the dose container disk,the at least one airway disk comprising a plurality of circumferentiallyspaced apart airway channels, wherein the at least one airway diskincludes a first airway disk and a second airway disk, the first airwaydisk residing below the dose container disk and the second airway diskresiding above the first airway disk with the dose container disktherebetween, wherein at least one of the airway channels of the firstairway disk is aligned with a corresponding at least one of the airwaychannels of the second airway disk with at least one dose containertherebetween to define cooperating airway channels, and wherein the dosecontainer assembly further comprises dry powder in the dose containers,and wherein the cooperating channels are cooperating pairs of airwaychannels that are in fluid communication, during dispensing of a dose ofdry powder in the at least one dose container held therebetween, andwherein the cooperating pairs of airway channels together with an openeddose container define a generally U shape airflow path with long sidesof the U corresponding to each airway channel and being oriented toextend in a radial direction across the first and second airway disks.15. A dry powder dose container assembly, comprising: a dose containerdisk having opposing upper and lower primary surfaces and a plurality ofcircumferentially spaced apart dose containers; and at least one airwaydisk residing above or below the dose container disk, the at least oneairway disk comprising a plurality of circumferentially spaced apartairway channels, wherein the circumferentially spaced apart airwaychannels of the at least one airway disk extend in a radial directionand each airway channel defines a discrete corresponding dry powder exitport, and wherein the respective discrete dry powder exit ports arecircumferentially spaced apart and reside on an outer or inner perimeterof the at least one airway disk.
 16. A dry powder dose containerassembly according to claim 8, wherein the at least one airway disk isattached to the dose container disk to be able to rotate therewith, andwherein the airway channels extend radially across the at least oneairway disk and are positioned relative to the dose container disk sothat at least one airway channel is aligned with at least one dosecontainer.
 17. An inhaler, comprising: an inhaler body with aninhalation port and a piercing mechanism; and a dry powder dosecontainer assembly in the inhaler, comprising: a dose container diskhaving opposing upper and lower primary surfaces and a plurality ofcircumferentially spaced apart dose containers; and at least one airwaydisk residing above or below the dose container disk, the at least oneairway disk comprising a plurality of circumferentially spaced apartairway channels; a plurality of circumferentially spaced apart dosecontainer apertures extending through the dose container disk thatdefine at least a portion of the dose containers; a first sealantresiding over the dose container apertures; and a second sealantresiding under the dose container apertures wherein, in operation, thepiercing mechanism is configured to pierce the first and second sealantlayers, and remain in or retract from a respective dose containeraperture, and wherein the inhaler comprises a lever in communicationwith a biasing post that resides in the inhaler proximate an outerperimeter or inner perimeter of the dose container assembly, wherein inresponse to movement of the lever, the biasing post pushes the dosecontainer assembly radially against either a mouthpiece or an exitairflow path member in fluid communication with the mouthpiece.
 18. Aninhaler, comprising: an inhaler body with an inhalation port and apiercing mechanism; and a dry powder dose container assembly in theinhaler, comprising: a dose container disk having opposing upper andlower primary surfaces and a plurality of circumferentially spaced apartdose containers; and an upper airway disk and a lower airway disksandwiching the dose container disk therebetween, the upper and lowerairway disk comprising a plurality of circumferentially spaced apartairway channels: a plurality of circumferentially spaced apart dosecontainer apertures extending through the dose container disk thatdefine at least a portion of the dose containers; a first sealantresiding over the dose container apertures; and a second sealantresiding under the dose container apertures wherein, in operation, thepiercing mechanism is configured to pierce the first and second sealantlayers, and remain in or retract from a respective dose containeraperture, and wherein the inhaler has an indexing mechanism incommunication with the dose container assembly, and wherein the piercingmechanism and indexing mechanism are configured to index/pierce/deliveror pierce/deliver/index to isolate, from an inhalation path, an upper orlower airway channel associated with the at least one airway disk incommunication with a corresponding opened dose container.
 19. Aninhaler, comprising: an inhaler body with an inhalation port and apiercing mechanism; and a dry powder dose container assembly in theinhaler, comprising: a dose container disk having opposing upper andlower primary surfaces and a plurality of circumferentially spaced apartdose containers; and at least one airway disk residing above or belowthe dose container disk, the at least one airway disk comprising aplurality of circumferentially spaced apart airway channels; a pluralityof circumferentially spaced apart dose container apertures extendingthrough the dose container disk that define at least a portion of thedose containers; a first sealant residing over the dose containerapertures; and a second sealant residing under the dose containerapertures wherein, in operation; the piercing mechanism is configured topierce the first and second sealant layers, and remain in or retractfrom a respective dose container aperture, and wherein the dosecontainer disk includes a first row of circumferentially spaced apartapertures at a first radius and a second row of circumferentially spacedapart apertures at a second radius so that the first and second rows areconcentric with respect to a center of the disk, and wherein thepiercing mechanism includes first and second piercers, the first piercerconfigured to pierce the sealant over and under the respective dosecontainer apertures in the first row, and the second piercer configuredto pierce the sealant over and under the respective dose containerapertures in the second row.
 20. The inhaler combination of claim 19,wherein the piercer mechanism comprises a corkscrew piercer configuredto pierce the sealants with a straight vertical non-rotational movement.21. An inhaler, comprising: an inhaler body with an inhalation port anda piercing mechanism; and a dry powder dose container assembly in theinhaler, comprising: a dose container disk having opposing upper andlower primary surfaces and a plurality of circumferentially spaced apartdose containers; and at least one airway disk residing above or belowthe dose container disk, the at least one airway disk comprising aplurality of circumferentially spaced apart airway channels; a pluralityof circumferentially spaced apart dose container apertures extendingthrough the dose container disk that define at least a portion of thedose containers; a first sealant residing over the dose containerapertures; and a second sealant residing under the dose containerapertures wherein, in operation, the piercing mechanism is configured topierce the first and second sealant layers, and remain in or retractfrom a respective dose container aperture, and wherein the piercermechanism is configured to serially alternate between rows to pierce thesealants over and under a dose container in a first row of dosecontainer apertures, then pierce the sealants over and under a dosecontainer in a second row of dose container apertures.
 22. The inhalerclaim 21, wherein the piercing mechanism comprises a fluted piercerconfigured to pierce the sealants.
 23. An inhaler, comprising: aninhaler body with an inhalation port and a piercing mechanism; and a drypowder dose container assembly in the inhaler, comprising: a dosecontainer disk having opposing upper and lower primary surfaces and aplurality of circumferentially spaced apart dose containers; and atleast one airway disk residing above or below the dose container disk,the at least one airway disk comprising a plurality of circumferentiallyspaced apart airway channels; a plurality of circumferentially spacedapart dose container apertures extending through the dose container diskthat define at least a portion of the dose containers; a first sealantresiding over the dose container apertures; and a second sealantresiding under the dose container apertures wherein, in operation, thepiercing mechanism is configured to pierce the first and second sealantlayers, and remain in or retract from a respective dose containeraperture, wherein the piercing mechanism comprises a fluted piercerconfigured to pierce the sealants, wherein the fluted piercer comprisesthree or four lobes, and wherein one of the at least one airway diskshas circumferentially spaced apart apertures, one aperture residing overor under a respective dose container, the airway disk apertures having aperimeter shape corresponding to the three or four lobes, respectively,of the fluted piercer.
 24. The inhaler of claim 19, wherein the piercingmechanism comprises a solid piercer.
 25. The inhaler of claim 18,wherein the dose container comprises a dry powder having apharmaceutically active agent, and wherein the agent comprises one ormore of the following bronchodilators: albuterol, salmeterol, ephedrine,adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol,phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol,terbutaline, isoetharine, tulobuterol, or(+4-amino-3,5-dichloro-α-[[6-[2-(2-pyridinyl)ethoxy]hexyl]methyl]benzenemethanol;wherein the bronchodilator may be used in the form of salts, esters orsolvates to thereby, optimize the activity and/or stability of themedicament.
 26. A dry powder inhaler, comprising: a circular dosecontainer disk having a plurality of circumferentially spaced apart drypowder chambers; and a first airway disk residing above or below thedose container disk, the airway disk comprising a plurality ofcircumferentially spaced apart radially oriented airway channels, onechannel aligned with one of the dose container disk chambers in whichairflow passes through one or more 90 degree turns with dry powderentrained therein to thereby inhibit agglomeration.
 27. A dry powderinhaler, comprising: an inhaler body with an inhalation port; a dosecontainer assembly held in the inhaler body, the dose container assemblycomprising: a dose container disk having a plurality ofcircumferentially spaced apart apertures; a lower airway disk having aplurality of airway channels with upwardly extending sidewalls residingunder the dose container disk: an upper airway disk having a pluralityof airway channels with downwardly extending sidewalls residing abovethe dose container disk, wherein the upper and lower airway disks holdthe dose container disk therebetween, wherein the upper and lower airwaydisk channels are aligned to define a plurality of cooperating pair ofairway channels, each cooperating pair of airway channels associatedwith a dose container aperture, and wherein each cooperating pair ofchannels are configured to serially communicate with the inhalationport, wherein the upper airway disk includes an upper surface that has aplurality of circumferentially spaced apart apertures, one residing overa corresponding dose disk aperture whereby the airway disks airwaychannels define a plurality of spaced apart inhalation delivery pathsthat individually communicate with the inhalation port; a dose containeropening mechanism in the inhaler body configured to open a dosecontainer held by the dose container disk in a dispensing position inthe inhaler; and an indexing mechanism in the inhaler body configured torotate the dose container assembly to place a dose container held by thedose container disk in the dispensing position.
 28. A dry powderinhaler, comprising: an inhaler body with an inhalation port; a dosecontainer assembly held in the inhaler body, the dose container assemblycomprising a dose container disk having a plurality of circumferentiallyspaced apart apertures, and an airway disk having a plurality of airwaychannels with upwardly or downwardly extending sidewalls residing underor over the dose container disk, each of the airway channels being incommunication with at least one dose container aperture, wherein thedose container apertures are arranged in a staggered concentricconfiguration of inner and outer rows, and wherein the airway diskairway channels define a plurality of spaced apart inhalation deliverypaths that individually communicate with the inhalation port; a dosecontainer opening mechanism in the inhaler body configured to open adose container held by the dose container disk in a dispensing positionin the inhaler; and an indexing mechanism in the inhaler body configuredto rotate the dose container assembly to place a dose container held bythe dose container disk in the dispensing position.
 29. An inhaleraccording to claim 28, wherein the airway disk includescircumferentially spaced apart apertures, one residing over or under arespective dose container aperture, wherein the dose container assemblyfurther comprises a first sealant that resides over the upper surface ofthe dose container disk and a second sealant that resides over the lowersurface of the dose container disk to close the dose container apertureswith dry powder held therein and define dose containers, and wherein thedose container opening mechanism comprises a piercer that is configuredto pierce the first and second sealant layers.
 30. An inhaler accordingto claim 28, wherein the dose container opening mechanism is configuredto pierce the first and second sealants associated with a dose containerand occlude or seal a respective airway and/or airway disk apertureduring inhalation.
 31. An inhaler according to claim 27, wherein thedose container opening mechanism comprises a member that is configuredto substantially seal the upper airway disk aperture during aninhalation.
 32. A dry powder inhaler, comprising: an inhaler body withan inhalation port; a dose container assembly held in the inhaler body,the dose container assembly comprising: a dose container disk havingopposing upper and lower primary surfaces and a plurality ofcircumferentially spaced apart apertures with first and second sealantlayers attached to the upper and lower primary surfaces of the dosecontainer disk to define a respective floor and ceiling of the dosecontainer apertures to form sealed dose containers holding dry powdertherein; an upper airway disk residing over the dose container disk, theupper airway disk comprising a plurality of circumferentially spacedapart airway channels with downwardly extending sidewalls; and a lowerairway disk residing under the dose container disk, the lower airwaydisk comprising a plurality of circumferentially spaced apart airwaychannels with upwardly extending sidewalls, wherein pairs of the lowerairway disk channels and the upper airway disk channels are aligned withat least one corresponding dose container therebetween; a dose containeropening mechanism configured to open a dose container in a dispensingposition in the inhaler; and an indexing mechanism configured to rotatethe dose container assembly to place dose containers into the dispensingposition.
 33. A dry powder inhaler, comprising: a circular dosecontainer disk assembly having a plurality of circumferentially spacedapart radially oriented airway channels aligned with a plurality ofcircumferentially spaced apart sealed dose containers with dry powdertherein held in first and second concentric rows of different radius,wherein prior to active dispensing, the airway channels are drug free,and wherein one end of the airway channels define exit flow paths thatare in communication with a mouthpiece; a mouthpiece configured toengage an outer and/or inner perimeter of the dose container disk toserially communicate with the circumferentially spaced apart airwaychannels to entrain dry powder from an opened dose container to deliverdry powder to a user; a piercing mechanism configured to open the dosecontainers to release the dry powder therein; and an indexing mechanismin communication with the circular dose disk assembly.